N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor

ABSTRACT

The present invention relates to N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating diseases that respond to modulation of the serotonin 5-HT 6  receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. patent application Ser. No.12/770,837, filed on Apr. 30, 2010, which claims priority to U.S.Provisional Patent Application No. 61/174,054, filed on Apr. 30, 2009,the contents of all of which are herein incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to N-phenyl-(piperazinyl orhomopiperazinyl)-benzenesulfonamide orbenzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds,pharmaceutical compositions containing them, and their use in therapy.The compounds possess valuable therapeutic properties and areparticularly suitable for treating diseases that respond to modulationof the serotonin 5-HT₆ receptor.

Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter andlocal hormone, is formed by the hydroxylation and decarboxylation oftryptophan. The greatest concentration is found in the enterochromaffincells of the gastrointestinal tract, the remainder being predominantlypresent in platelets and in the Central Nervous System (CNS). 5-HT isimplicated in a vast array of physiological and pathophysiologicalpathways. In the periphery, it contracts a number of smooth muscles andinduces endothelium-dependent vasodilation. In the CNS, it is believedto be involved in a wide range of functions, including the control ofappetite, mood, anxiety, hallucinations, sleep, vomiting and painperception.

Neurons that secrete 5-HT are termed serotonergic. The function of 5-HTis exerted upon its interaction with specific (serotonergic) neurons.Until now, seven types of 5-HT receptors have been identified: 5-HT,(with subtypes 5-HT_(1A), 5-HT_(1B), 5-HT_(1D), 5-HT_(1E) and5-HT_(1F)), 5-HT₂(with subtypes 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C)),5-HT₃, 5-HT₄, 5-HT₅ (with subtypes 5-HT_(5A) and 5-HT_(5B)), 5-HT₆ and5-HT₇. Most of these receptors are coupled to G-proteins that affect theactivities of either adenylate cyclase or phospholipase Cγ.

The human 5-HT₆ receptors are positively coupled to adenylyl cyclase.They are distributed throughout the limbic, striatal and corticalregions of the brain and show a high affinity to antipsychotics.

The modulation of the 5-HT₆ receptor by suitable substances is expectedto improve certain disorders including cognitive dysfunctions, such as adeficit in memory, cognition and learning, in particular associated withAlzheimer's disease, age-related cognitive decline and mild cognitiveimpairment, attention deficit disorder/hyperactivity syndrome,personality disorders, such as schizophrenia, in particular cognitivedeficits related with schizophrenia, affective disorders such asdepression, anxiety and obsessive compulsive disorders, motion or motordisorders such as Parkinson's disease and epilepsy, migraine, sleepdisorders (including disturbances of the Circadian rhythm), feedingdisorders, such as anorexia and bulimia, certain gastrointestinaldisorders such as Irritable Bowel Syndrome, diseases associated withneurodegeneration, such as stroke, spinal or head trauma and headinjuries, such as hydrocephalus, addiction diseases and obesity (seee.g. A. Meneses, Drug News Perspect 14(7) (2001) pp. 396-400 andliterature cited therein; J. Pharmacol. Sci. Vol. 101 (Suppl. 1), 2006,p. 124. Modulators of the 5HT₆-receptor such as PRX-07034 (EpixPharmaceuticals) have been found in preclinical and clinical studies tobe particular useful in the treatment of cognitive dysfunctions, inparticular associated with Alzheimer's disease or schizophrenia or inthe treatment of obesity (see e.g.http://www.epixpharma.com/products/prx-07034.asp).

WO 98/027081, WO 99/02502, WO 00/12623, WO 00/12073, US 2003/0069233, WO02/08179, WO 02/92585, WO 2006/010629 describe certainbenzenesulfonanilide compounds having 5HT₆ receptor antagonist activityand suggest the use of these compounds for the treatment of medicaldisorders which are susceptible to the treatment with 5HT₆ receptorantagonists such as certain CNS disorders, drug abuse, ADHD, obesity andtype II diabetes. WO 2004/080986 and WO 03/014097 describe certaindiarylsulfone compounds, suggesting the use of these compounds for thetreatment of medical disorders which are susceptible to the treatmentwith 5HT₆ receptor antagonists such as certain CNS disorders, drugabuse, ADHD, obesity and type II diabetes. WO 2008087123 suggestscompounds having 5HT₆ receptor antagonist activity for preventingrelapse into addiction.

However, there is still an ongoing need for providing compounds havinghigh affinity for the 5-HT₆ receptor and which show high selectivity tothis receptor. In particular the compounds should have low affinity toadrenergic receptors, such as α₁-adrenergic receptor, histaminereceptors, such as H₁-receptor, and dopaminergic receptors, such asD₂-receptor, in order to avoid or reduce considerable side effectsassociated with modulation of these receptors, such as posturalhypotension, reflex tachycardia, potentiation of the antihypertensiveeffect of prazosin, terazosin, doxazosin and labetalol or dizzinessassociated to the blockade of the α₁-adrenergic receptor, weight gain,sedation, drowsiness or potentiation of central depressant drugsassociated to the blockade of the H₁-receptor, or extrapyramidalmovement disorder, such as dystonia, parkinsonism, akathisia, tardivedyskinesia or rabbit syndrome, or endocrine effects, such as prolactinelevation (galactorrhea, gynecomastia, menstruyl changes, sexualdysfunction in males), associated to the blockade of the D₂-receptor.

It is one object of the present invention to provide compounds whichhave a high affinity for the 5-HT₆ receptor. It is a further object ofthe present invention to provide compounds which selectively bind to the5-HT₆ receptor.

The compounds should also have good pharmacological profile, e.g. a goodbioavailability and/or a good metabolic stability.

SUMMARY OF THE INVENTION

The present invention relates to N-phenyl-(piperazinyl orhomopiperazinyl)-benzenesulfonamides orbenzenesulfonyl-phenyl-(piperazines or homopiperazines) of formula (I)or (I′)

-   wherein-   X is a bond or a group N—R⁴;-   R¹ is hydrogen or methyl;-   R² is hydrogen or methyl;-   R³ is hydrogen, C₁-C₃ alkyl (e.g. methyl), fluorine, C₁-C₂ alkoxy    (e.g. methoxy) or fluorinated C₁-C₂ alkoxy;-   R⁴ is hydrogen C₁-C₄ alkyl (e.g. methyl, ethyl, n-propyl,    isopropyl), C₃-C₄ cycloalkyl, or —CH₂—C₃-C₄ cycloalkyl (e.g.    cyclopropylmethyl);-   R⁵ is hydrogen, fluorine, chlorine, C₁-C₂ alkyl (e.g. methyl),    fluorinated C₁-C₂ alkyl, C₁-C₂ alkoxy (e.g. methoxy) or fluorinated    C₁-C₂ alkoxy;-   R⁶ is hydrogen, fluorine or chlorine; and-   n is 1 or 2,-   and physiologically tolerated acid addition salts and the N-oxides    thereof.

Said compounds, i.e., the N-phenyl-(piperazinyl orhomopiperazinyl)-benzenesulfonamides orbenzenesulfonyl-phenyl-piperazines or -homopiperazines and theirphysiologically tolerated acid addition salts and the N-oxides thereof,exhibit to a surprising and unexpected degree, a high binding affinityto the 5-HT₆ receptor and are thus useful as pharmaceuticals.

The present invention thus further relates to the compounds of formula(I) or (I′) for use in therapy.

The present invention also relates to pharmaceutical compositions whichcomprise a compound of formula (I) or (I′) and, optionally, aphysiologically acceptable carrier and/or an auxiliary substance.

In particular, said compounds, i.e., the N-phenyl-(piperazinyl orhomopiperazinyl)-benzenesulfonamides orbenzenesulfonyl-phenyl-(piperazines or homopiperazines) and theirphysiologically tolerated acid addition salts and the N-oxides thereof,are modulators of the 5-HT₆ receptor.

The present invention thus further relates to the compounds of formula(I) or (I′) for use in modulating the 5-HT₆ receptor.

The present invention also relates to the use of the compounds offormula (I) or (I′) in the manufacture of a medicament for modulatingthe 5-HT₆ receptor and corresponding methods of modulating the 5-HT₆receptor.

Modulators of the 5-HT₆ receptor and in particular antagonists of the5-HT₆ receptor are known to be useful in treating a variety ofdisorders.

The present invention thus further relates to the compounds of formula(I) or (I′) for use in treating said disorders.

The present invention also relates to the use of the compounds offormula (I) or (I′) in the manufacture of a medicament for treating saiddisorders and corresponding methods of treating said disorders.

DETAILED DESCRIPTION OF THE INVENTION

The disorders diseases which are susceptible to treatment with acompound of the formula (I) or (I′) include, e.g., disorders anddiseases of the central nervous system, in particular cognitivedysfunctions, such as a deficit in memory, cognition and learning, inparticular associated with Alzheimer's disease, age-related cognitivedecline and mild cognitive impairment, attention deficitdisorder/hyperactivity syndrome (ADHD), personality disorders, such asschizophrenia, in particular cognitive deficits related withschizophrenia, affective disorders such as depression, anxiety andobsessive compulsive disorders, motion or motor disorders such asParkinson's disease and epilepsy, migraine, sleep disorders (includingdisturbances of the Circadian rhythm), feeding disorders, such asanorexia and bulimia, certain gastrointestinal disorders such asIrritable Bowel Syndrome, diseases associated with neurodegeneration,such as stroke, spinal or head trauma and head injuries, includinghydrocephalus, drug addiction and obesity.

Provided the compounds of the formula (I) or (I′) of a givenconstitution may exist in different spatial arrangements, for example ifthey possess one or more centers of asymmetry, polysubstituted rings ordouble bonds, or as different tautomers, the invention also relates toenantiomeric mixtures, in particular racemates, diastereomeric mixturesand tautomeric mixtures, preferably, however, the respective essentiallypure enantiomers (ennatiomerically pure), diastereomers and tautomers ofthe compounds of formula (I) or (I′) and/or of their salts and/or theirN-oxides.

The invention also relates to physiologically tolerated salts of thecompounds of the formula (I) or (I′), especially acid addition saltswith physiologically tolerated acids. Examples of suitablephysiologically tolerated organic and inorganic acids are hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid,C₁-C₄-alkylsulfonic acids, such as methanesulfonic acid, aromaticsulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid,oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid,adipic acid and benzoic acid. Other utilizable acids are described inFortschritte der Arzneimittelforschung [Advances in drug research],Volume 10, pages 224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966.

The invention also relates to N-oxides of the compounds of the formula(I) or (I′), provided that those compounds contain a basic nitrogenatom, such as the nitrogen atom of the piperazine moiety.

The organic moieties mentioned in the above definitions of the variablesare—like the term halogen—collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

As used herein, C₁-C₄ alkyl is a straight-chain or branched alkyl grouphaving 1, 2, 3 or 4 carbon atoms. Examples of such a group includemethyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl,1-methylpropyl (=2-butyl), 2-methylpropyl (=isobutyl) and1,1-dimethylethyl (=tert.-butyl).

As used herein, fluorinated C₁-C₂ alkyl is a straight-chain alkyl grouphaving 1 or 2 carbon atoms, wherein at least one hydrogen atom, e.g. 1,2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine. Examples of sucha group include fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,1,1,2,2-tetrafluoroethyl and 1,1,2,2,2-pentafluoroethyl.

As used herein, C₁-C₂ alkoxy is a straight-chain alkyl group having 1 or2 carbon atoms which is bound to the remainder of the molecule via anoxygen atom, i.e., methoxy and ethoxy.

As used herein, fluorinated C₁-C₂ alkoxy is an alkoxy group as definedabove, wherein at least one, e.g. 1, 2, 3, 4 or 5 hydrogen atoms arereplaced by fluorine atoms. Examples of such a group are fluoromethoxy,difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy and 1,1,2,2-tetrafluoroethoxy.

As used herein, C₃-C₄-cycloalkyl is a cycloaliphatic radical having from3 to 4 carbon atoms, i.e. cyclopropyl and cyclobutyl.

With respect to the compounds' capability of modulating the 5-HT₆receptor, the variables X, R¹, R², R³, R⁴, R⁵, R⁶ and n preferably havethe following meanings which, when taken alone or in combination,represent particular embodiments of the compounds of the formula (I) or(I′).

X is a bond or a group N—R⁴. A first preferred embodiment of theinvention relates to compounds of the formula I or I′, to theirpharmacologically tolerated salts and to the N-oxides thereof, wherein Xis a group N—R⁴.

R¹ is hydrogen or methyl. A second preferred embodiment of the inventionrelates to compounds of the formula I or I′, to their pharmacologicallytolerated salts and to the N-oxides thereof, wherein R¹ is hydrogen.Another embodiment of the invention relates to compounds of the formulaI or I′, to their pharmacologically tolerated salts and to the N-oxidesthereof, wherein R¹ is methyl.

R² is hydrogen or methyl. A third preferred embodiment of the inventionrelates to compounds of the formula I or I′, to their pharmacologicallytolerated salts and to the N-oxides thereof, wherein R² is hydrogen.

Another embodiment of the invention relates to compounds of the formulaI or I′, wherein R² is methyl. If R² is methyl, the carbon atom thatcarries R² creates a center of chirality. Thus, a specific embodiment ofthe invention relates to compounds of the formula I or I′, to theirpharmacologically tolerated salts and to the N-oxides thereof, whereinR² is methyl and wherein the carbon atom that carries R² hasS-configuration. Another specific embodiment of the invention relates tocompounds of the formula I or I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein R² is methyl and wherein thecarbon atom that carries R² has R-configuration.

Likewise preferred are mixtures of compounds of the present invention,wherein the carbon atom that carries R² has S-configuration orR-configuration, respectively. These mixtures may contain equal amountsor non-equal amounts of the compound I, or equal amounts or non-equalamounts of the compound I′, respectively, that have R-configuration withregard to the moiety CH—R² and of the compound I or I′ that haveS-configuration with regard to CH—R².

The term “enantiomerically pure” means that the mixture contains therespective compound in an entaniomeric excess of at least 80%, inparticular at least 90% (ee).

R³ is hydrogen, C₁-C₃ alkyl (e.g. methyl), fluorine, C₁-C₂ alkoxy (e.g.methoxy or ethoxy) or fluorinated C₁-C₂ alkoxy.

Preference is given to compounds of the formula I or I′, to theirpharmacologically tolerated salts and to the N-oxides thereof, whereinR³ is methyl or methoxy, difluoromethoxy or trifluoromethoxy, inparticular methyl or methoxy, and most preferably methyl. The inventionalso relates to compounds of the formula I or I′, to theirpharmacologically tolerated salts and to the N-oxides thereof, whereinR³ is hydrogen or fluorine, in particular hydrogen. The invention alsorelates to compounds of the formula I or I′, to their pharmacologicallytolerated salts and to the N-oxides thereof, wherein R³ is methoxy orethoxy.

R⁴ is hydrogen, C₁-C₄ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl),C₃-C₄ cycloalkyl, or C₃-C₄ cycloalkyl-CH₂— (e.g. cyclopropylmethyl).

Preference is given to compounds of the formula I or I′, to theirpharmacologically tolerated salts and to the N-oxides thereof, whereinR⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl or cyclopropylmethyl.More preference is given to the compounds of the present invention,wherein R⁴ is hydrogen.

R⁵ is hydrogen, fluorine, C₁-C₂ alkyl (e.g. methyl), fluorinated C₁-C₂alkyl, C₁-C₂ alkoxy (e.g. methoxy) or fluorinated C₁-C₂ alkoxy.

R⁵ is preferably selected from the group consisting of hydrogen,fluorine, methyl, trifluoromethyl, methoxy, difluoromethoxy andtrifluoromethoxy and more preferably from hydrogen, methoxy anddifluoromethoxy. Likewise, preference is given to the compounds of theformula I or I′, wherein R⁵ is chlorine. In a particular preferredembodiment of the invention, R⁵ is hydrogen. In another particularpreferred embodiment of the invention, R⁵ is selected from fluorine,methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxyand more preferably from methyl, methoxy and difluoromethoxy. Likewise,more preference is given to the compounds of the formula I or I′,wherein R⁵ is fluorine. Likewise, more preference is given to thecompounds of the formula I or I′, wherein R⁵ is chlorine.

R⁶ is hydrogen, fluorine or chlorine, preferably hydrogen or fluorine.In a particular preferred embodiment of the invention, R⁶ is hydrogen.In another particular embodiment of the invention R⁶ is different fromhydrogen, in particular fluorine. If R⁶ is different from hydrogen it ispreferably located in the 5- or 6-position of the benzene ring.

Preference is given to those compounds of the formula I or I′, to theirpharmacologically tolerated salts and to the N-oxides thereof, whereinR³ is methyl or methoxy and R⁶ is hydrogen, or R³ is methyl or methoxyand R⁶ is fluorine being located in the 5- or 6-position of the benzenering, or both R³ and R⁶ are hydrogen or R³ is hydrogen and R⁶ isfluorine being located in the 5- or 6-position of the benzene ring.

According to a further particular embodiment, R⁵ and R⁶ are hydrogen, R³is selected from the group consisting of C₁-C₂ alkyl (e.g. methyl) andC₁-C₂ alkoxy (e.g. methoxy), and R⁴ is selected from the groupconsisting of hydrogen, C₁-C₄ alkyl (e.g. methyl, ethyl, n-propyl,isopropyl), or cyclopropylmethyl.

n is 1 or 2, thus forming a piperazine or a homopiperazine moiety.Preference is give to n being 1, i.e. compounds having a piperazinemoiety.

A particular preferred embodiment Ia of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in    particular methyl or methoxy; and-   R⁴ is hydrogen.

A further particular preferred embodiment Ib of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in    particular methyl or methoxy; and-   R⁴ is methyl.

A further particular preferred embodiment Ic of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is methyl;-   R² is hydrogen;-   R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in    particular methyl or methoxy; and-   R⁴ is hydrogen.

A further particular preferred embodiment Id of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is methyl;-   R² is hydrogen;-   R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, in    particular methyl or methoxy; and-   R⁴ is methyl.

A further particular preferred embodiment Ia of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is methoxy or ethoxy; and-   R⁴ is hydrogen.

A further particular preferred embodiment Ia of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is methyl;-   R² is hydrogen;-   R³ is methoxy or ethoxy; and-   R⁴ is hydrogen.

A particular preferred embodiment Ie of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is hydrogen or fluorine, in particular hydrogen; and-   R⁴ is hydrogen.

A further particular preferred embodiment If of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is hydrogen or fluorine, in particular hydrogen; and-   R⁴ is methyl.

A further particular preferred embodiment Ig of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is methyl;-   R² is hydrogen;-   R³ is hydrogen or fluorine, in particular hydrogen; and-   R⁴ is hydrogen.

A further particular preferred embodiment Ih of the invention relates tocompounds of the formula I, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

-   R¹ is methyl;-   R² is hydrogen;-   R³ is hydrogen or fluorine, in particular hydrogen; and-   R⁴ is methyl.

A further particular preferred embodiment 1 h of the invention relatesto compounds of the formula I, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is methoxy or ethoxy; and-   R⁴ is hydrogen.

A further particular preferred embodiment 1 h of the invention relatesto compounds of the formula I, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

-   R¹ is methyl;-   R² is hydrogen;-   R³ is methoxy or ethoxy; and-   R⁴ is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,preference is given to those, where the radicals R⁵ and R⁶ in formula Iare both hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis hydrogen and where the radical R⁶ in formula I is fluorine, which islocated in the 5-position or in the 6-position of the benzene ring.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis methoxy and where the radical R⁶ in formula I is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis methoxy and where the radical R⁶ in formula I is fluorine, which islocated in the 5-position or in the 6-position of the benzene ring.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis difluoromethoxy and where the radical R⁶ in formula I is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis difluoromethoxy and where the radical R⁶ in formula I is fluorine,which is located in the 5-position or in the 6-position of the benzenering.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis chlorine and where the radical R⁶ in formula I is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis fluorine and where the radical R⁶ in formula I is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis difluoromethoxy and where the radical R⁶ in formula I is hydrogen.

Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih,likewise preference is given to those, where the radical R⁵ in formula Iis methyl and where the radical R⁶ in formula I is hydrogen.

A particular preferred embodiment I′a of the invention relates tocompounds of the formula I′, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

R¹ is hydrogen;R² is hydrogen;R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, inparticular methyl or methoxy; andR⁴ is hydrogen.

A further particular preferred embodiment I′b of the invention relatesto compounds of the formula I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

R¹ is hydrogen;R² is methyl;R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, inparticular methyl or methoxy; andR⁴ is hydrogen.

A further particular preferred embodiment I′c of the invention relatesto compounds of the formula I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

R¹ is hydrogen;R² is hydrogen;R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, inparticular methyl or methoxy; andR⁴ is methyl.

A further particular preferred embodiment I′d of the invention relatesto compounds of the formula I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

R¹ is hydrogen;R² is methyl;R³ is methyl, methoxy, difluoromethoxy or trifluoromethoxy, inparticular methyl or methoxy; andR⁴ is methyl.

A particular preferred embodiment I′e of the invention relates tocompounds of the formula I′, to their pharmacologically tolerated saltsand to the N-oxides thereof, wherein

R¹ is hydrogen;R² is hydrogen;R³ is hydrogen or fluorine, in particular hydrogen; andR⁴ is hydrogen.

A further particular preferred embodiment I′f of the invention relatesto compounds of the formula I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

R¹ is hydrogen;R² is methyl;R³ is hydrogen or fluorine, in particular hydrogen; andR⁴ is hydrogen.

A further particular preferred embodiment I′g of the invention relatesto compounds of the formula I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

R¹ is hydrogen;R² is hydrogen;R³ is hydrogen or fluorine, in particular hydrogen; andR⁴ is methyl.

A further particular preferred embodiment I′h of the invention relatesto compounds of the formula I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

R¹ is hydrogen;R² is methyl;R³ is hydrogen or fluorine, in particular hydrogen; andR⁴ is methyl.

Amongst the compounds of embodiments I′a, I′b, I′c, I′d, I′e, I′g andI′h, preference is given to those, where the radicals R⁵ and R⁶ informula I′ are both hydrogen.

Amongst the compounds of embodiments I′a, I′b, I′c, I′d, I′e, I′g andI′h, likewise preference is given to those, where the radical R⁵ informula I is hydrogen and where the radical R⁶ in formula I′ isfluorine, which is located in the 5-position or in the 6-position of thebenzene ring.

Amongst the compounds of the formula I, in particular amongst thecompounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, particularpreference is given to those, wherein the OCHF₂-radical is located onthe benzene ring in the meta-position with respect to X. Amongst thesecompounds, particular preference is given to those compounds of theformula I, wherein R⁵ is hydrogen. Amongst these compounds, likewisepreference is given to those compounds of the formula I, wherein R⁵ isdifferent from hydrogen and in particular selected from fluorine,chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy andtrifluoromethoxy and more preferably from methyl, methoxy anddifluoromethoxy, and located in the para-position, with respect to X, orin the para-position, with respect to the OCHF₂-radical.

Amongst the compounds of the formula I, in particular amongst thecompounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewisepreference is given to those, wherein the OCHF₂-radical is located onthe benzene ring in the ortho-position with respect to X. Amongst thesecompounds, particular preference is given to those compounds of theformula I, wherein R⁵ is hydrogen. Amongst these compounds, likewisepreference is given to those compounds of the formula I, wherein R⁵ isdifferent from hydrogen and in particular selected from fluorine,chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy andtrifluoromethoxy and more preferably from methyl, methoxy anddifluoromethoxy, and located in the para-position, with respect to X, orin the para-position, with respect to the OCHF₂-radical.

Amongst the compounds of the formula I, in particular amongst thecompounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and Ih, likewisepreference is given to those, wherein the OCHF₂-radical is located onthe benzene ring in the para-position with respect to X. Amongst thesecompounds, particular preference is given to those compounds of theformula I, wherein R⁵ is hydrogen. Amongst these compounds, likewisepreference is given to those compounds of the formula I, wherein R⁵ isdifferent from hydrogen and in particular selected from fluorine,chlorine, methyl, trifluoromethyl, methoxy, difluoromethoxy andtrifluoromethoxy and more preferably from methyl, methoxy anddifluoromethoxy, and located in the meta-position, with respect to X.

Amongst the compounds of the formula I′, in particular amongst thecompounds of embodiments I′a, I′b, I′c, I′d, I′e, and I′g, particularpreference is given to those, wherein X is attached to the benzene ringin the α-position with respect to the 1,3-dioxole ring. Amongst thesecompounds, particular preference is given to those compounds of theformula I′, wherein R⁵ is hydrogen.

Amongst the compounds of the formula I′, in particular amongst thecompounds of embodiments I′a, I′b, I′c, I′d, I′e, and I′g, particularpreference is given to those, wherein X is attached to the benzene ringin the B-position with respect to the 1,3-dioxole ring. Amongst thesecompounds, particular preference is given to those compounds of theformula I′, wherein R⁵ is hydrogen.

A particular preferred embodiment of the invention relates to compoundsof the formula I or I′, to their pharmacologically tolerated salts andto the N-oxides thereof, wherein

-   X is a bond or a group N—R⁴;-   R¹ is hydrogen or methyl;-   R² is hydrogen or methyl, in particular hydrogen;-   R³ is hydrogen, C₁-C₂ alkyl, fluorine, C₁-C₂ alkoxy or fluorinated    C₁-C₂ alkoxy, preferably hydrogen, methyl, methoxy, difluoromethoxy    or trifluoromethoxy, in particular hydrogen, methyl or methoxy;-   R⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl or    cyclopropylmethyl;-   R⁵ is hydrogen, fluorine, chlorine, methyl, trifluoromethyl,    methoxy, difluoromethoxy and trifluoromethoxy and more preferably    hydrogen, methyl or methoxy;-   R⁶ is hydrogen or fluorine, which is located in the 5- or 6-position    of the benzene ring; and-   n is 1 or 2.

A further particular preferred embodiment of the invention relates tocompounds of the formula I or I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

-   X is a bond or a group N—R⁴;-   R¹ is hydrogen or methyl, preferably hydrogen;-   R² is hydrogen;-   R³ is hydrogen, C₁-C₂ alkyl or C₁-C₂ alkoxy, preferably hydrogen,    methyl or methoxy, in particular methyl or methoxy;-   R⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl or    cyclopropylmethyl, preferably hydrogen;-   R⁵ is hydrogen, chlorine, fluorine, difluoromethoxy, methyl or    methoxy, preferably hydrogen, methyl or methoxy, in particular    hydrogen;-   R⁶ is hydrogen; and-   n is 1 or 2, preferably 1.

A further particular preferred embodiment of the invention relates tocompounds of the formula I or I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

-   X is a group N—R⁴;-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is C₁-C₂ alkyl or C₁-C₂ alkoxy, preferably methyl or methoxy;-   R⁴ is hydrogen;-   R⁵ is hydrogen;-   R⁶ is hydrogen; and-   n is 1.

A further particular preferred embodiment of the invention relates tocompounds of the formula I or I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

-   X is a group N—R⁴;-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is C₁-C₂ alkyl or C₁-C₂ alkoxy, preferably methyl or methoxy;-   R⁴ is hydrogen;-   R⁵ is chlorine;-   R⁶ is hydrogen; and-   n is 1.

A further particular preferred embodiment of the invention relates tocompounds of the formula I or I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

-   X is a group N—R⁴;-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is C₁-C₂ alkyl or C₁-C₂ alkoxy, preferably methyl or methoxy;-   R⁴ is hydrogen;-   R⁵ is fluorine;-   R⁶ is hydrogen; and-   n is 1.

A further particular preferred embodiment of the invention relates tocompounds of the formula I or I′, to their pharmacologically toleratedsalts and to the N-oxides thereof, wherein

-   X is a group N—R⁴;-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is C₁-C₂ alkyl or C₁-C₂ alkoxy, preferably methyl or methoxy;-   R⁴ is hydrogen;-   R⁵ is difluoromethoxy;-   R⁶ is hydrogen; and-   n is 1.

Examples of compounds according to the present invention are thecompounds of the formula I, their pharmacologically tolerated salts andthe N-oxides thereof, wherein R⁶ is hydrogen, and the meanings of X, R¹,R², R³, R⁴ and R⁵ and the position of R⁵ and of the moiety OCHF₂ on thebenzene ring is given in the following table A:

TABLE A No. n R¹ R² R³ X OCHF₂* R⁵ 1. 1 H H OCH₃ NH ortho H 2. 1 H HOCH₃ NH meta H 3. 1 H H OCH₃ NH para H 4. 1 H H OCH₃ NH ortho CH₃ (parato NH) 5. 1 H H OCH₃ NH ortho CH₃ (para to OCHF₂) 6. 1 H H OCH₃ NH metaOCH₃ (para to NH) 7. 1 H H OCH₃ NH meta OCH₃ (para to OCHF₂) 8. 1 H HOCH₃ NH meta CH₃ (para to NH) 9. 1 H H OCH₃ NH ortho Cl (para to NH) 10.1 H H OCH₃ NH ortho Cl (para to OCHF₂) 11. 1 H H OCH₃ NH ortho F (parato NH) 12. 1 H H OCH₃ NH ortho F (para to OCHF₂) 13. 1 H H OCH₃ NH metaOCHF₂ (para to NH) 14. 1 CH₃ H OCH₃ NH ortho H 15. 1 CH₃ H OCH₃ NH metaH 16. 1 CH₃ H OCH₃ NH para H 17. 1 CH₃ H OCH₃ NH ortho CH₃ (para to NH)18. 1 CH₃ H OCH₃ NH ortho CH₃ (para to OCHF₂) 19. 1 CH₃ H OCH₃ NH metaOCH₃ (para to NH) 20. 1 CH₃ H OCH₃ NH meta OCH₃ (para to OCHF₂) 21. 1CH₃ H OCH₃ NH meta CH₃ (para to NH) 22. 1 CH₃ H OCH₃ NH ortho Cl (parato NH) 23. 1 CH₃ H OCH₃ NH ortho Cl (para to OCHF₂) 24. 1 CH₃ H OCH₃ NHortho F (para to NH) 25. 1 CH₃ H OCH₃ NH ortho F (para to OCHF₂) 26. 1CH₃ H OCH₃ NH meta OCHF₂ (para to NH) 27. 1 H H OCH₃ NCH₃ ortho H 28. 1H H OCH₃ NCH₃ meta H 29. 1 H H OCH₃ NCH₃ para H 30. 1 H H OCH₃ NCH₃ortho CH₃ (para to X) 31. 1 H H OCH₃ NCH₃ ortho CH₃ (para to OCHF₂) 32.1 H H OCH₃ NCH₃ meta OCH₃ (para to X) 33. 1 H H OCH₃ NCH₃ meta OCH₃(para to OCHF₂) 34. 1 H H OCH₃ NCH₃ meta CH₃ (para to X) 35. 1 H H OCH₃NCH₃ ortho Cl (para to X) 36. 1 H H OCH₃ NCH₃ ortho Cl (para to OCHF₂)37. 1 H H OCH₃ NCH₃ ortho F (para to X) 38. 1 H H OCH₃ NCH₃ ortho F(para to OCHF₂) 39. 1 H H OCH₃ NCH₃ meta OCHF₂ (para to X) 40. 1 CH₃ HOCH₃ NCH₃ ortho H 41. 1 CH₃ H OCH₃ NCH₃ meta H 42. 1 CH₃ H OCH₃ NCH₃para H 43. 1 CH₃ H OCH₃ NCH₃ ortho CH₃ (para to X) 44. 1 CH₃ H OCH₃ NCH₃ortho CH₃ (para to OCHF₂) 45. 1 CH₃ H OCH₃ NCH₃ meta OCH₃ (para to X)46. 1 CH₃ H OCH₃ NCH₃ meta OCH₃ (para to OCHF₂) 47. 1 CH₃ H OCH₃ NCH₃meta CH₃ (para to X) 48. 1 CH₃ H OCH₃ NCH₃ ortho Cl (para to X) 49. 1CH₃ H OCH₃ NCH₃ ortho Cl (para to OCHF₂) 50. 1 CH₃ H OCH₃ NCH₃ ortho F(para to X) 51. 1 CH₃ H OCH₃ NCH₃ ortho F (para to OCHF₂) 52. 1 CH₃ HOCH₃ NCH₃ meta OCHF₂ (para to X) 53. 1 H H OCH₃ NCH₂CH₃ ortho H 54. 1 HH OCH₃ NCH₂CH₃ meta H 55. 1 H H OCH₃ NCH₂CH₃ para H 56. 1 H H OCH₃NCH₂CH₃ ortho CH₃ (para to X) 57. 1 H H OCH₃ NCH₂CH₃ ortho CH₃ (para toOCHF₂) 58. 1 H H OCH₃ NCH₂CH₃ meta OCH₃ (para to X) 59. 1 H H OCH₃NCH₂CH₃ meta OCH₃ (para to OCHF₂) 60. 1 H H OCH₃ NCH₂CH₃ meta CH₃ (parato X) 61. 1 CH₃ H OCH₃ NCH₂CH₃ ortho H 62. 1 CH₃ H OCH₃ NCH₂CH₃ meta H63. 1 CH₃ H OCH₃ NCH₂CH₃ para H 64. 1 CH₃ H OCH₃ NCH₂CH₃ ortho CH₃ (parato X) 65. 1 CH₃ H OCH₃ NCH₂CH₃ ortho CH₃ (para to OCHF₂) 66. 1 CH₃ HOCH₃ NCH₂CH₃ meta OCH₃ (para to X) 67. 1 CH₃ H OCH₃ NCH₂CH₃ meta OCH₃(para to OCHF₂) 68. 1 CH₃ H OCH₃ NCH₂CH₃ meta CH₃ (para to X) 69. 1 H HOCH₃ N(CH₂)₂CH₃ ortho H 70. 1 H H OCH₃ N(CH₂)₂CH₃ meta H 71. 1 H H OCH₃N(CH₂)₂CH₃ para H 72. 1 H H OCH₃ N(CH₂)₂CH₃ ortho CH₃ (para to X) 73. 1H H OCH₃ N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 74. 1 H H OCH₃ N(CH₂)₂CH₃meta OCH₃ (para to X) 75. 1 H H OCH₃ N(CH₂)₂CH₃ meta OCH₃ (para toOCHF₂) 76. 1 H H OCH₃ N(CH₂)₂CH₃ meta CH₃ (para to X) 77. 1 CH₃ H OCH₃N(CH₂)₂CH₃ ortho H 78. 1 CH₃ H OCH₃ N(CH₂)₂CH₃ meta H 79. 1 CH₃ H OCH₃N(CH₂)₂CH₃ para H 80. 1 CH₃ H OCH₃ N(CH₂)₂CH₃ ortho CH₃ (para to X) 81.1 CH₃ H OCH₃ N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 82. 1 CH₃ H OCH₃N(CH₂)₂CH₃ meta OCH₃ (para to X) 83. 1 CH₃ H OCH₃ N(CH₂)₂CH₃ meta OCH₃(para to OCHF₂) 84. 1 CH₃ H OCH₃ N(CH₂)₂CH₃ meta CH₃ (para to X) 85. 1 HH OCH₃ N(CH₂)-cyclopropyl ortho H 86. 1 H H OCH₃ N(CH₂)-cyclopropyl metaH 87. 1 H H OCH₃ N(CH₂)-cyclopropyl para H 88. 1 H H OCH₃N(CH₂)-cyclopropyl ortho CH₃ (para to X) 89. 1 H H OCH₃N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 90. 1 H H OCH₃N(CH₂)-cyclopropyl meta OCH₃ (para to X) 91. 1 H H OCH₃N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 92. 1 H H OCH₃N(CH₂)-cyclopropyl meta CH₃ (para to X) 93. 1 CH₃ H OCH₃N(CH₂)-cyclopropyl ortho H 94. 1 CH₃ H OCH₃ N(CH₂)-cyclopropyl meta H95. 1 CH₃ H OCH₃ N(CH₂)-cyclopropyl para H 96. 1 CH₃ H OCH₃N(CH₂)-cyclopropyl ortho CH₃ (para to X) 97. 1 CH₃ H OCH₃N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 98. 1 CH₃ H OCH₃N(CH₂)-cyclopropyl meta OCH₃ (para to X) 99. 1 CH₃ H OCH₃N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 100. 1 CH₃ H OCH₃N(CH₂)-cyclopropyl meta CH₃ (para to X) 101. 1 H H OCH₃ bond ortho H102. 1 H H OCH₃ bond meta H 103. 1 H H OCH₃ bond para H 104. 1 H H OCH₃bond ortho CH₃ (para to X) 105. 1 H H OCH₃ bond ortho CH₃ (para toOCHF₂) 106. 1 H H OCH₃ bond meta OCH₃ (para to X) 107. 1 H H OCH₃ bondmeta OCH₃ (para to OCHF₂) 108. 1 H H OCH₃ bond meta CH₃ (para to X) 109.1 CH₃ H OCH₃ bond ortho H 110. 1 CH₃ H OCH₃ bond meta H 111. 1 CH₃ HOCH₃ bond para H 112. 1 CH₃ H OCH₃ bond ortho CH₃ (para to X) 113. 1 CH₃H OCH₃ bond ortho CH₃ (para to OCHF₂) 114. 1 CH₃ H OCH₃ bond meta OCH₃(para to X) 115. 1 CH₃ H OCH₃ bond meta OCH₃ (para to OCHF₂) 116. 1 CH₃H OCH₃ bond meta CH₃ (para to X) 117. 2 H H OCH₃ NH ortho H 118. 2 H HOCH₃ NH meta H 119. 2 H H OCH₃ NH para H 120. 2 H H OCH₃ NH ortho CH₃(para to NH) 121. 2 H H OCH₃ NH ortho CH₃ (para to OCHF₂) 122. 2 H HOCH₃ NH meta OCH₃ (para to NH) 123. 2 H H OCH₃ NH meta OCH₃ (para toOCHF₂) 124. 2 H H OCH₃ NH meta CH₃ (para to NH) 125. 2 H H OCH₃ NH orthoCl (para to NH) 126. 2 H H OCH₃ NH ortho Cl (para to OCHF₂) 127. 2 H HOCH₃ NH ortho F (para to NH) 128. 2 H H OCH₃ NH ortho F (para to OCHF₂)129. 2 H H OCH₃ NH meta OCHF₂ (para to NH) 130. 2 CH₃ H OCH₃ NH ortho H131. 2 CH₃ H OCH₃ NH meta H 132. 2 CH₃ H OCH₃ NH para H 133. 2 CH₃ HOCH₃ NH ortho CH₃ (para to NH) 134. 2 CH₃ H OCH₃ NH ortho CH₃ (para toOCHF₂) 135. 2 CH₃ H OCH₃ NH meta OCH₃ (para to NH) 136. 2 CH₃ H OCH₃ NHmeta OCH₃ (para to OCHF₂) 137. 2 CH₃ H OCH₃ NH meta CH₃ (para to NH)138. 2 CH₃ H OCH₃ NH ortho Cl (para to NH) 139. 2 CH₃ H OCH₃ NH ortho Cl(para to OCHF₂) 140. 2 CH₃ H OCH₃ NH ortho F (para to NH) 141. 2 CH₃ HOCH₃ NH ortho F (para to OCHF₂) 142. 2 CH₃ H OCH₃ NH meta OCHF₂ (para toNH) 143. 2 H H OCH₃ NCH₃ ortho H 144. 2 H H OCH₃ NCH₃ meta H 145. 2 H HOCH₃ NCH₃ para H 146. 2 H H OCH₃ NCH₃ ortho CH₃ (para to X) 147. 2 H HOCH₃ NCH₃ ortho CH₃ (para to OCHF₂) 148. 2 H H OCH₃ NCH₃ meta OCH₃ (parato X) 149. 2 H H OCH₃ NCH₃ meta OCH₃ (para to OCHF₂) 150. 2 H H OCH₃NCH₃ meta CH₃ (para to X) 151. 2 H H OCH₃ NCH₃ ortho Cl (para to X) 152.2 H H OCH₃ NCH₃ ortho Cl (para to OCHF₂) 153. 2 H H OCH₃ NCH₃ ortho F(para to X) 154. 2 H H OCH₃ NCH₃ ortho F (para to OCHF₂) 155. 2 H H OCH₃NCH₃ meta OCHF₂ (para to X) 156. 2 CH₃ H OCH₃ NCH₃ ortho H 157. 2 CH₃ HOCH₃ NCH₃ meta H 158. 2 CH₃ H OCH₃ NCH₃ para H 159. 2 CH₃ H OCH₃ NCH₃ortho CH₃ (para to X) 160. 2 CH₃ H OCH₃ NCH₃ ortho CH₃ (para to OCHF₂)161. 2 CH₃ H OCH₃ NCH₃ meta OCH₃ (para to X) 162. 2 CH₃ H OCH₃ NCH₃ metaOCH₃ (para to OCHF₂) 163. 2 CH₃ H OCH₃ NCH₃ meta CH₃ (para to X) 164. 2CH₃ H OCH₃ NCH₃ ortho Cl (para to X) 165. 2 CH₃ H OCH₃ NCH₃ ortho Cl(para to OCHF₂) 166. 2 CH₃ H OCH₃ NCH₃ ortho F (para to X) 167. 2 CH₃ HOCH₃ NCH₃ ortho F (para to OCHF₂) 168. 2 CH₃ H OCH₃ NCH₃ meta OCHF₂(para to X) 169. 2 H H OCH₃ NCH₂CH₃ ortho H 170. 2 H H OCH₃ NCH₂CH₃ metaH 171. 2 H H OCH₃ NCH₂CH₃ para H 172. 2 H H OCH₃ NCH₂CH₃ ortho CH₃ (parato X) 173. 2 H H OCH₃ NCH₂CH₃ ortho CH₃ (para to OCHF₂) 174. 2 H H OCH₃NCH₂CH₃ meta OCH₃ (para to X) 175. 2 H H OCH₃ NCH₂CH₃ meta OCH₃ (para toOCHF₂) 176. 2 H H OCH₃ NCH₂CH₃ meta CH₃ (para to X) 177. 2 CH₃ H OCH₃NCH₂CH₃ ortho H 178. 2 CH₃ H OCH₃ NCH₂CH₃ meta H 179. 2 CH₃ H OCH₃NCH₂CH₃ para H 180. 2 CH₃ H OCH₃ NCH₂CH₃ ortho CH₃ (para to X) 181. 2CH₃ H OCH₃ NCH₂CH₃ ortho CH₃ (para to OCHF₂) 182. 2 CH₃ H OCH₃ NCH₂CH₃meta OCH₃ (para to X) 183. 2 CH₃ H OCH₃ NCH₂CH₃ meta OCH₃ (para toOCHF₂) 184. 2 CH₃ H OCH₃ NCH₂CH₃ meta CH₃ (para to X) 185. 2 H H OCH₃N(CH₂)₂CH₃ ortho H 186. 2 H H OCH₃ N(CH₂)₂CH₃ meta H 187. 2 H H OCH₃N(CH₂)₂CH₃ para H 188. 2 H H OCH₃ N(CH₂)₂CH₃ ortho CH₃ (para to X) 189.2 H H OCH₃ N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 190. 2 H H OCH₃N(CH₂)₂CH₃ meta OCH₃ (para to X) 191. 2 H H OCH₃ N(CH₂)₂CH₃ meta OCH₃(para to OCHF₂) 192. 2 H H OCH₃ N(CH₂)₂CH₃ meta CH₃ (para to X) 193. 2CH₃ H OCH₃ N(CH₂)₂CH₃ ortho H 194. 2 CH₃ H OCH₃ N(CH₂)₂CH₃ meta H 195. 2CH₃ H OCH₃ N(CH₂)₂CH₃ para H 196. 2 CH₃ H OCH₃ N(CH₂)₂CH₃ ortho CH₃(para to X) 197. 2 CH₃ H OCH₃ N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 198.2 CH₃ H OCH₃ N(CH₂)₂CH₃ meta OCH₃ (para to X) 199. 2 CH₃ H OCH₃N(CH₂)₂CH₃ meta OCH₃ (para to OCHF₂) 200. 2 CH₃ H OCH₃ N(CH₂)₂CH₃ metaCH₃ (para to X) 201. 2 H H OCH₃ N(CH₂)-cyclopropyl ortho H 202. 2 H HOCH₃ N(CH₂)-cyclopropyl meta H 203. 2 H H OCH₃ N(CH₂)-cyclopropyl para H204. 2 H H OCH₃ N(CH₂)-cyclopropyl ortho CH₃ (para to X) 205. 2 H H OCH₃N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 206. 2 H H OCH₃N(CH₂)-cyclopropyl meta OCH₃ (para to X) 207. 2 H H OCH₃N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 208. 2 H H OCH₃N(CH₂)-cyclopropyl meta CH₃ (para to X) 209. 2 CH₃ H OCH₃N(CH₂)-cyclopropyl mrtho H 210. 2 CH₃ H OCH₃ N(CH₂)-cyclopropyl meta H211. 2 CH₃ H OCH₃ N(CH₂)-cyclopropyl para H 212. 2 CH₃ H OCH₃N(CH₂)-cyclopropyl ortho CH₃ (para to X) 213. 2 CH₃ H OCH₃N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 214. 2 CH₃ H OCH₃N(CH₂)-cyclopropyl meta OCH₃ (para to X) 215. 2 CH₃ H OCH₃N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 216. 2 CH₃ H OCH₃N(CH₂)-cyclopropyl meta CH₃ (para to X) 217. 2 H H OCH₃ bond ortho H218. 2 H H OCH₃ bond meta H 219. 2 H H OCH₃ bond para H 220. 2 H H OCH₃bond ortho CH₃ (para to X) 221. 2 H H OCH₃ bond ortho CH₃ (para toOCHF₂) 222. 2 H H OCH₃ bond meta OCH₃ (para to X) 223. 2 H H OCH₃ bondmeta OCH₃ (para to OCHF₂) 224. 2 H H OCH₃ bond meta CH₃ (para to X) 225.2 CH₃ H OCH₃ bond ortho H 226. 2 CH₃ H OCH₃ bond meta H 227. 2 CH₃ HOCH₃ bond para H 228. 2 CH₃ H OCH₃ bond ortho CH₃ (para to X) 229. 2 CH₃H OCH₃ bond ortho CH₃ (para to OCHF₂) 230. 2 CH₃ H OCH₃ bond meta OCH₃(para to X) 231. 2 CH₃ H OCH₃ bond meta OCH₃ (para to OCHF₂) 232. 2 CH₃H OCH₃ bond meta CH₃ (para to X) 233. 1 H H OCHF₂ NH ortho H 234. 1 H HOCHF₂ NH meta H 235. 1 H H OCHF₂ NH para H 236. 1 H H OCHF₂ NH ortho CH₃(para to NH) 237. 1 H H OCHF₂ NH ortho CH₃ (para to OCHF₂) 238. 1 H HOCHF₂ NH meta OCH₃ (para to NH) 239. 1 H H OCHF₂ NH meta OCH₃ (para toOCHF₂) 240. 1 H H OCHF₂ NH meta CH₃ (para to NH) 241. 1 H H OCHF₂ NHortho Cl (para to NH) 242. 1 H H OCHF₂ NH ortho Cl (para to OCHF₂) 243.1 H H OCHF₂ NH ortho F (para to NH) 244. 1 H H OCHF₂ NH ortho F (para toOCHF₂) 245. 1 H H OCHF₂ NH meta OCHF₂ (para to NH) 246. 1 CH₃ H OCHF₂ NHortho H 247. 1 CH₃ H OCHF₂ NH meta H 248. 1 CH₃ H OCHF₂ NH para H 249. 1CH₃ H OCHF₂ NH ortho CH₃ (para to NH) 250. 1 CH₃ H OCHF₂ NH ortho CH₃(para to OCHF₂) 251. 1 CH₃ H OCHF₂ NH meta OCH₃ (para to NH) 252. 1 CH₃H OCHF₂ NH meta OCH₃ (para to OCHF₂) 253. 1 CH₃ H OCHF₂ NH meta CH₃(para to NH) 254. 1 CH₃ H OCHF₂ NH ortho Cl (para to NH) 255. 1 CH₃ HOCHF₂ NH ortho Cl (para to OCHF₂) 256. 1 CH₃ H OCHF₂ NH ortho F (para toNH) 257. 1 CH₃ H OCHF₂ NH ortho F (para to OCHF₂) 258. 1 CH₃ H OCHF₂ NHmeta OCHF₂ (para to NH) 259. 1 H H OCHF₂ NCH₃ ortho H 260. 1 H H OCHF₂NCH₃ meta H 261. 1 H H OCHF₂ NCH₃ para H 262. 1 H H OCHF₂ NCH₃ ortho CH₃(para to X) 263. 1 H H OCHF₂ NCH₃ ortho CH₃ (para to OCHF₂) 264. 1 H HOCHF₂ NCH₃ meta OCH₃ (para to X) 265. 1 H H OCHF₂ NCH₃ meta OCH₃ (parato OCHF₂) 266. 1 H H OCHF₂ NCH₃ meta CH₃ (para to X) 267. 1 H H OCHF₂NCH₃ ortho Cl (para to X) 268. 1 H H OCHF₂ NCH₃ ortho Cl (para to OCHF₂)269. 1 H H OCHF₂ NCH₃ ortho F (para to X) 270. 1 H H OCHF₂ NCH₃ ortho F(para to OCHF₂) 271. 1 H H OCHF₂ NCH₃ meta OCHF₂ (para to X) 272. 1 CH₃H OCHF₂ NCH₃ ortho H 273. 1 CH₃ H OCHF₂ NCH₃ meta H 274. 1 CH₃ H OCHF₂NCH₃ para H 275. 1 CH₃ H OCHF₂ NCH₃ ortho CH₃ (para to X) 276. 1 CH₃ HOCHF₂ NCH₃ ortho CH₃ (para to OCHF₂) 277. 1 CH₃ H OCHF₂ NCH₃ meta OCH₃(para to X) 278. 1 CH₃ H OCHF₂ NCH₃ meta OCH₃ (para to OCHF₂) 279. 1 CH₃H OCHF₂ NCH₃ meta CH₃ (para to X) 280. 1 CH₃ H OCHF₂ NCH₃ ortho Cl (parato X) 281. 1 CH₃ H OCHF₂ NCH₃ ortho Cl (para to OCHF₂) 282. 1 CH₃ HOCHF₂ NCH₃ ortho F (para to X) 283. 1 CH₃ H OCHF₂ NCH₃ ortho F (para toOCHF₂) 284. 1 CH₃ H OCHF₂ NCH₃ meta OCHF₂ (para to X) 285. 1 H H OCHF₂NCH₂CH₃ ortho H 286. 1 H H OCHF₂ NCH₂CH₃ meta H 287. 1 H H OCHF₂ NCH₂CH₃para H 288. 1 H H OCHF₂ NCH₂CH₃ ortho CH₃ (para to X) 289. 1 H H OCHF₂NCH₂CH₃ ortho CH₃ (para to OCHF₂) 290. 1 H H OCHF₂ NCH₂CH₃ meta OCH₃(para to X) 291. 1 H H OCHF₂ NCH₂CH₃ meta OCH₃ (para to OCHF₂) 292. 1 HH OCHF₂ NCH₂CH₃ meta CH₃ (para to X) 293. 1 CH₃ H OCHF₂ NCH₂CH₃ ortho H294. 1 CH₃ H OCHF₂ NCH₂CH₃ meta H 295. 1 CH₃ H OCHF₂ NCH₂CH₃ para H 296.1 CH₃ H OCHF₂ NCH₂CH₃ ortho CH₃ (para to X) 297. 1 CH₃ H OCHF₂ NCH₂CH₃ortho CH₃ (para to OCHF₂) 298. 1 CH₃ H OCHF₂ NCH₂CH₃ meta OCH₃ (para toX) 299. 1 CH₃ H OCHF₂ NCH₂CH₃ meta OCH₃ (para to OCHF₂) 300. 1 CH₃ HOCHF₂ NCH₂CH₃ meta CH₃ (para to X) 301. 1 H H OCHF₂ N(CH₂)₂CH₃ ortho H302. 1 H H OCHF₂ N(CH₂)₂CH₃ meta H 303. 1 H H OCHF₂ N(CH₂)₂CH₃ para H304. 1 H H OCHF₂ N(CH₂)₂CH₃ ortho CH₃ (para to X) 305. 1 H H OCHF₂N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 306. 1 H H OCHF₂ N(CH₂)₂CH₃ metaOCH₃ (para to X) 307. 1 H H OCHF₂ N(CH₂)₂CH₃ meta OCH₃ (para to OCHF₂)308. 1 H H OCHF₂ N(CH₂)₂CH₃ meta CH₃ (para to X) 309. 1 CH₃ H OCHF₂N(CH₂)₂CH₃ ortho H 310. 1 CH₃ H OCHF₂ N(CH₂)₂CH₃ meta H 311. 1 CH₃ HOCHF₂ N(CH₂)₂CH₃ para H 312. 1 CH₃ H OCHF₂ N(CH₂)₂CH₃ ortho CH₃ (para toX) 313. 1 CH₃ H OCHF₂ N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 314. 1 CH₃ HOCHF₂ N(CH₂)₂CH₃ meta OCH₃ (para to X) 315. 1 CH₃ H OCHF₂ N(CH₂)₂CH₃meta OCH₃ (para to OCHF₂) 316. 1 CH₃ H OCHF₂ N(CH₂)₂CH₃ meta CH₃ (parato X) 317. 1 H H OCHF₂ N(CH₂)-cyclopropyl ortho H 318. 1 H H OCHF₂N(CH₂)-cyclopropyl meta H 319. 1 H H OCHF₂ N(CH₂)-cyclopropyl para H320. 1 H H OCHF₂ N(CH₂)-cyclopropyl ortho CH₃ (para to X) 321. 1 H HOCHF₂ N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 322. 1 H H OCHF₂N(CH₂)-cyclopropyl meta OCH₃ (para to X) 323. 1 H H OCHF₂N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 324. 1 H H OCHF₂N(CH₂)-cyclopropyl meta CH₃ (para to X) 325. 1 CH₃ H OCHF₂N(CH₂)-cyclopropyl ortho H 326. 1 CH₃ H OCHF₂ N(CH₂)-cyclopropyl meta H327. 1 CH₃ H OCHF₂ N(CH₂)-cyclopropyl para H 328. 1 CH₃ H OCHF₂N(CH₂)-cyclopropyl ortho CH₃ (para to X) 329. 1 CH₃ H OCHF₂N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 330. 1 CH₃ H OCHF₂N(CH₂)-cyclopropyl meta OCH₃ (para to X) 331. 1 CH₃ H OCHF₂N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 332. 1 CH₃ H OCHF₂N(CH₂)-cyclopropyl meta CH₃ (para to X) 333. 1 H H OCHF₂ bond ortho H334. 1 H H OCHF₂ bond meta H 335. 1 H H OCHF₂ bond para H 336. 1 H HOCHF₂ bond ortho CH₃ (para to X) 337. 1 H H OCHF₂ bond ortho CH₃ (parato OCHF₂) 338. 1 H H OCHF₂ bond meta OCH₃ (para to X) 339. 1 H H OCHF₂bond meta OCH₃ (para to OCHF₂) 340. 1 H H OCHF₂ bond meta CH₃ (para toX) 341. 1 CH₃ H OCHF₂ bond ortho H 342. 1 CH₃ H OCHF₂ bond meta H 343. 1CH₃ H OCHF₂ bond para H 344. 1 CH₃ H OCHF₂ bond ortho CH₃ (para to X)345. 1 CH₃ H OCHF₂ bond ortho CH₃ (para to OCHF₂) 346. 1 CH₃ H OCHF₂bond meta OCH₃ (para to X) 347. 1 CH₃ H OCHF₂ bond meta OCH₃ (para toOCHF₂) 348. 1 CH₃ H OCHF₂ bond meta CH₃ (para to X) 349. 2 H H OCHF₂ NHortho H 350. 2 H H OCHF₂ NH meta H 351. 2 H H OCHF₂ NH para H 352. 2 H HOCHF₂ NH ortho CH₃ (para to NH) 353. 2 H H OCHF₂ NH ortho CH₃ (para toOCHF₂) 354. 2 H H OCHF₂ NH meta OCH₃ (para to NH) 355. 2 H H OCHF₂ NHmeta OCH₃ (para to OCHF₂) 356. 2 H H OCHF₂ NH meta CH₃ (para to NH) 357.2 H H OCHF₂ NH ortho Cl (para to NH) 358. 2 H H OCHF₂ NH ortho Cl (parato OCHF₂) 359. 2 H H OCHF₂ NH ortho F (para to NH) 360. 2 H H OCHF₂ NHortho F (para to OCHF₂) 361. 2 H H OCHF₂ NH meta OCHF₂ (para to NH) 362.2 CH₃ H OCHF₂ NH ortho H 363. 2 CH₃ H OCHF₂ NH meta H 364. 2 CH₃ H OCHF₂NH para H 365. 2 CH₃ H OCHF₂ NH ortho CH₃ (para to NH) 366. 2 CH₃ HOCHF₂ NH ortho CH₃ (para to OCHF₂) 367. 2 CH₃ H OCHF₂ NH meta OCH₃ (parato NH) 368. 2 CH₃ H OCHF₂ NH meta OCH₃ (para to OCHF₂) 369. 2 CH₃ HOCHF₂ NH meta CH₃ (para to NH) 370. 2 CH₃ H OCHF₂ NH ortho Cl (para toNH) 371. 2 CH₃ H OCHF₂ NH ortho Cl (para to OCHF₂) 372. 2 CH₃ H OCHF₂ NHortho F (para to NH) 373. 2 CH₃ H OCHF₂ NH ortho F (para to OCHF₂) 374.2 CH₃ H OCHF₂ NH meta OCHF₂ (para to NH) 375. 2 H H OCHF₂ NCH₃ ortho H376. 2 H H OCHF₂ NCH₃ meta H 377. 2 H H OCHF₂ NCH₃ para H 378. 2 H HOCHF₂ NCH₃ ortho CH₃ (para to X) 379. 2 H H OCHF₂ NCH₃ ortho CH₃ (parato OCHF₂) 380. 2 H H OCHF₂ NCH₃ meta OCH₃ (para to X) 381. 2 H H OCHF₂NCH₃ meta OCH₃ (para to OCHF₂) 382. 2 H H OCHF₂ NCH₃ meta CH₃ (para toX) 383. 2 H H OCHF₂ NCH₃ ortho Cl (para to X) 384. 2 H H OCHF₂ NCH₃ortho Cl (para to OCHF₂) 385. 2 H H OCHF₂ NCH₃ ortho F (para to X) 386.2 H H OCHF₂ NCH₃ ortho F (para to OCHF₂) 387. 2 H H OCHF₂ NCH₃ metaOCHF₂ (para to X) 388. 2 CH₃ H OCHF₂ NCH₃ ortho H 389. 2 CH₃ H OCHF₂NCH₃ meta H 390. 2 CH₃ H OCHF₂ NCH₃ para H 391. 2 CH₃ H OCHF₂ NCH₃ orthoCH₃ (para to X) 392. 2 CH₃ H OCHF₂ NCH₃ ortho CH₃ (para to OCHF₂) 393. 2CH₃ H OCHF₂ NCH₃ meta OCH₃ (para to X) 394. 2 CH₃ H OCHF₂ NCH₃ meta OCH₃(para to OCHF₂) 395. 2 CH₃ H OCHF₂ NCH₃ meta CH₃ (para to X) 396. 2 CH₃H OCHF₂ NCH₃ ortho Cl (para to X) 397. 2 CH₃ H OCHF₂ NCH₃ ortho Cl (parato OCHF₂) 398. 2 CH₃ H OCHF₂ NCH₃ ortho F (para to X) 399. 2 CH₃ H OCHF₂NCH₃ ortho F (para to OCHF₂) 400. 2 CH₃ H OCHF₂ NCH₃ meta OCHF₂ (para toX) 401. 2 H H OCHF₂ NCH₂CH₃ ortho H 402. 2 H H OCHF₂ NCH₂CH₃ meta H 403.2 H H OCHF₂ NCH₂CH₃ para H 404. 2 H H OCHF₂ NCH₂CH₃ ortho CH₃ (para toX) 405. 2 H H OCHF₂ NCH₂CH₃ ortho CH₃ (para to OCHF₂) 406. 2 H H OCHF₂NCH₂CH₃ meta OCH₃ (para to X) 407. 2 H H OCHF₂ NCH₂CH₃ meta OCH₃ (parato OCHF₂) 408. 2 H H OCHF₂ NCH₂CH₃ meta CH₃ (para to X) 409. 2 CH₃ HOCHF₂ NCH₂CH₃ ortho H 410. 2 CH₃ H OCHF₂ NCH₂CH₃ meta H 411. 2 CH₃ HOCHF₂ NCH₂CH₃ para H 412. 2 CH₃ H OCHF₂ NCH₂CH₃ ortho CH₃ (para to X)413. 2 CH₃ H OCHF₂ NCH₂CH₃ ortho CH₃ (para to OCHF₂) 414. 2 CH₃ H OCHF₂NCH₂CH₃ meta OCH₃ (para to X) 415. 2 CH₃ H OCHF₂ NCH₂CH₃ meta OCH₃ (parato OCHF₂) 416. 2 CH₃ H OCHF₂ NCH₂CH₃ meta CH₃ (para to X) 417. 2 H HOCHF₂ N(CH₂)₂CH₃ ortho H 418. 2 H H OCHF₂ N(CH₂)₂CH₃ meta H 419. 2 H HOCHF₂ N(CH₂)₂CH₃ para H 420. 2 H H OCHF₂ N(CH₂)₂CH₃ ortho CH₃ (para toX) 421. 2 H H OCHF₂ N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 422. 2 H HOCHF₂ N(CH₂)₂CH₃ meta OCH₃ (para to X) 423. 2 H H OCHF₂ N(CH₂)₂CH₃ metaOCH₃ (para to OCHF₂) 424. 2 H H OCHF₂ N(CH₂)₂CH₃ meta CH₃ (para to X)425. 2 CH₃ H OCHF₂ N(CH₂)₂CH₃ ortho H 426. 2 CH₃ H OCHF₂ N(CH₂)₂CH₃ metaH 427. 2 CH₃ H OCHF₂ N(CH₂)₂CH₃ para H 428. 2 CH₃ H OCHF₂ N(CH₂)₂CH₃ortho CH₃ (para to X) 429. 2 CH₃ H OCHF₂ N(CH₂)₂CH₃ ortho CH₃ (para toOCHF₂) 430. 2 CH₃ H OCHF₂ N(CH₂)₂CH₃ meta OCH₃ (para to X) 431. 2 CH₃ HOCHF₂ N(CH₂)₂CH₃ meta OCH₃ (para to OCHF₂) 432. 2 CH₃ H OCHF₂ N(CH₂)₂CH₃meta CH₃ (para to X) 433. 2 H H OCHF₂ N(CH₂)-cyclopropyl ortho H 434. 2H H OCHF₂ N(CH₂)-cyclopropyl meta H 435. 2 H H OCHF₂ N(CH₂)-cyclopropylpara H 436. 2 H H OCHF₂ N(CH₂)-cyclopropyl ortho CH₃ (para to X) 437. 2H H OCHF₂ N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 438. 2 H H OCHF₂N(CH₂)-cyclopropyl meta OCH₃ (para to X) 439. 2 H H OCHF₂N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 440. 2 H H OCHF₂N(CH₂)-cyclopropyl meta CH₃ (para to X) 441. 2 CH₃ H OCHF₂N(CH₂)-cyclopropyl ortho H 442. 2 CH₃ H OCHF₂ N(CH₂)-cyclopropyl meta H443. 2 CH₃ H OCHF₂ N(CH₂)-cyclopropyl para H 444. 2 CH₃ H OCHF₂N(CH₂)-cyclopropyl ortho CH₃ (para to X) 445. 2 CH₃ H OCHF₂N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 446. 2 CH₃ H OCHF₂N(CH₂)-cyclopropyl meta OCH₃ (para to X) 447. 2 CH₃ H OCHF₂N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 448. 2 CH₃ H OCHF₂N(CH₂)-cyclopropyl meta CH₃ (para to X) 449. 2 H H OCHF₂ bond ortho H450. 2 H H OCHF₂ bond meta H 451. 2 H H OCHF₂ bond para H 452. 2 H HOCHF₂ bond ortho CH₃ (para to X) 453. 2 H H OCHF₂ bond ortho CH₃ (parato OCHF₂) 454. 2 H H OCHF₂ bond meta OCH₃ (para to X) 455. 2 H H OCHF₂bond meta OCH₃ (para to OCHF₂) 456. 2 H H OCHF₂ bond meta CH₃ (para toX) 457. 2 CH₃ H OCHF₂ bond ortho H 458. 2 CH₃ H OCHF₂ bond meta H 459. 2CH₃ H OCHF₂ bond para H 460. 2 CH₃ H OCHF₂ bond ortho CH₃ (para to X)461. 2 CH₃ H OCHF₂ bond ortho CH₃ (para to OCHF₂) 462. 2 CH₃ H OCHF₂bond meta OCH₃ (para to X) 463. 2 CH₃ H OCHF₂ bond meta OCH₃ (para toOCHF₂) 464. 2 CH₃ H OCHF₂ bond meta CH₃ (para to X) 465. 1 H H CH₃ NHortho H 466. 1 H H CH₃ NH meta H 467. 1 H H CH₃ NH para H 468. 1 H H CH₃NH ortho CH₃ (para to NH) 469. 1 H H CH₃ NH ortho CH₃ (para to OCHF₂)470. 1 H H CH₃ NH meta OCH₃ (para to NH) 471. 1 H H CH₃ NH meta OCH₃(para to OCHF₂) 472. 1 H H CH₃ NH meta CH₃ (para to NH) 473. 1 H H CH₃NH ortho Cl (para to NH) 474. 1 H H CH₃ NH ortho Cl (para to OCHF₂) 475.1 H H CH₃ NH ortho F (para to NH) 476. 1 H H CH₃ NH ortho F (para toOCHF₂) 477. 1 H H CH₃ NH meta OCHF₂ (para to NH) 478. 1 CH₃ H CH₃ NHortho H 479. 1 CH₃ H CH₃ NH meta H 480. 1 CH₃ H CH₃ NH para H 481. 1 CH₃H CH₃ NH ortho CH₃ (para to NH) 482. 1 CH₃ H CH₃ NH ortho CH₃ (para toOCHF₂) 483. 1 CH₃ H CH₃ NH meta OCH₃ (para to NH) 484. 1 CH₃ H CH₃ NHmeta OCH₃ (para to OCHF₂) 485. 1 CH₃ H CH₃ NH meta CH₃ (para to NH) 486.1 CH₃ H CH₃ NH ortho Cl (para to NH) 487. 1 CH₃ H CH₃ NH ortho Cl (parato OCHF₂) 488. 1 CH₃ H CH₃ NH ortho F (para to NH) 489. 1 CH₃ H CH₃ NHortho F (para to OCHF₂) 490. 1 CH₃ H CH₃ NH meta OCHF₂ (para to NH) 491.1 H H CH₃ NCH₃ ortho H 492. 1 H H CH₃ NCH₃ meta H 493. 1 H H CH₃ NCH₃para H 494. 1 H H CH₃ NCH₃ ortho CH₃ (para to X) 495. 1 H H CH₃ NCH₃ortho CH₃ (para to OCHF₂) 496. 1 H H CH₃ NCH₃ meta OCH₃ (para to X) 497.1 H H CH₃ NCH₃ meta OCH₃ (para to OCHF₂) 498. 1 H H CH₃ NCH₃ meta CH₃(para to X) 499. 1 H H CH₃ NCH₃ ortho Cl (para to X) 500. 1 H H CH₃ NCH₃ortho Cl (para to OCHF₂) 501. 1 H H CH₃ NCH₃ ortho F (para to X) 502. 1H H CH₃ NCH₃ ortho F (para to OCHF₂) 503. 1 H H CH₃ NCH₃ meta OCHF₂(para to X) 504. 1 CH₃ H CH₃ NCH₃ ortho H 505. 1 CH₃ H CH₃ NCH₃ meta H506. 1 CH₃ H CH₃ NCH₃ para H 507. 1 CH₃ H CH₃ NCH₃ ortho CH₃ (para to X)508. 1 CH₃ H CH₃ NCH₃ ortho CH₃ (para to OCHF₂) 509. 1 CH₃ H CH₃ NCH₃meta OCH₃ (para to X) 510. 1 CH₃ H CH₃ NCH₃ meta OCH₃ (para to OCHF₂)511. 1 CH₃ H CH₃ NCH₃ meta CH₃ (para to X) 512. 1 CH₃ H CH₃ NCH₃ orthoCl (para to X) 513. 1 CH₃ H CH₃ NCH₃ ortho Cl (para to OCHF₂) 514. 1 CH₃H CH₃ NCH₃ ortho F (para to X) 515. 1 CH₃ H CH₃ NCH₃ ortho F (para toOCHF₂) 516. 1 CH₃ H CH₃ NCH₃ meta OCHF₂ (para to X) 517. 1 H H CH₃NCH₂CH₃ ortho H 518. 1 H H CH₃ NCH₂CH₃ meta H 519. 1 H H CH₃ NCH₂CH₃para H 520. 1 H H CH₃ NCH₂CH₃ ortho CH₃ (para to X) 521. 1 H H CH₃NCH₂CH₃ ortho CH₃ (para to OCHF₂) 522. 1 H H CH₃ NCH₂CH₃ meta OCH₃ (parato X) 523. 1 H H CH₃ NCH₂CH₃ meta OCH₃ (para to OCHF₂) 524. 1 H H CH₃NCH₂CH₃ meta CH₃ (para to X) 525. 1 CH₃ H CH₃ NCH₂CH₃ ortho H 526. 1 CH₃H CH₃ NCH₂CH₃ meta H 527. 1 CH₃ H CH₃ NCH₂CH₃ para H 528. 1 CH₃ H CH₃NCH₂CH₃ ortho CH₃ (para to X) 529. 1 CH₃ H CH₃ NCH₂CH₃ ortho CH₃ (parato OCHF₂) 530. 1 CH₃ H CH₃ NCH₂CH₃ meta OCH₃ (para to X) 531. 1 CH₃ HCH₃ NCH₂CH₃ meta OCH₃ (para to OCHF₂) 532. 1 CH₃ H CH₃ NCH₂CH₃ meta CH₃(para to X) 533. 1 H H CH₃ N(CH₂)₂CH₃ ortho H 534. 1 H H CH₃ N(CH₂)₂CH₃meta H 535. 1 H H CH₃ N(CH₂)₂CH₃ para H 536. 1 H H CH₃ N(CH₂)₂CH₃ orthoCH₃ (para to X) 537. 1 H H CH₃ N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 538.1 H H CH₃ N(CH₂)₂CH₃ meta OCH₃ (para to X) 539. 1 H H CH₃ N(CH₂)₂CH₃meta OCH₃ (para to OCHF₂) 540. 1 H H CH₃ N(CH₂)₂CH₃ meta CH₃ (para to X)541. 1 CH₃ H CH₃ N(CH₂)₂CH₃ ortho H 542. 1 CH₃ H CH₃ N(CH₂)₂CH₃ meta H543. 1 CH₃ H CH₃ N(CH₂)₂CH₃ para H 544. 1 CH₃ H CH₃ N(CH₂)₂CH₃ ortho CH₃(para to X) 545. 1 CH₃ H CH₃ N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 546. 1CH₃ H CH₃ N(CH₂)₂CH₃ meta OCH₃ (para to X) 547. 1 CH₃ H CH₃ N(CH₂)₂CH₃meta OCH₃ (para to OCHF₂) 548. 1 CH₃ H CH₃ N(CH₂)₂CH₃ meta CH₃ (para toX) 549. 1 H H CH₃ N(CH₂)-cyclopropyl ortho H 550. 1 H H CH₃N(CH₂)-cyclopropyl meta H 551. 1 H H CH₃ N(CH₂)-cyclopropyl para H 552.1 H H CH₃ N(CH₂)-cyclopropyl ortho CH₃ (para to X) 553. 1 H H CH₃N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 554. 1 H H CH₃N(CH₂)-cyclopropyl meta OCH₃ (para to X) 555. 1 H H CH₃N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 556. 1 H H CH₃N(CH₂)-cyclopropyl meta CH₃ (para to X) 557. 1 CH₃ H CH₃N(CH₂)-cyclopropyl ortho H 558. 1 CH₃ H CH₃ N(CH₂)-cyclopropyl meta H559. 1 CH₃ H CH₃ N(CH₂)-cyclopropyl para H 560. 1 CH₃ H CH₃N(CH₂)-cyclopropyl ortho CH₃ (para to X) 561. 1 CH₃ H CH₃N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 562. 1 CH₃ H CH₃N(CH₂)-cyclopropyl meta OCH₃ (para to X) 563. 1 CH₃ H CH₃N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 564. 1 CH₃ H CH₃N(CH₂)-cyclopropyl meta CH₃ (para to X) 565. 1 H H CH₃ bond ortho H 566.1 H H CH₃ bond meta H 567. 1 H H CH₃ bond para H 568. 1 H H CH₃ bondortho CH₃ (para to X) 569. 1 H H CH₃ bond ortho CH₃ (para to OCHF₂) 570.1 H H CH₃ bond meta OCH₃ (para to X) 571. 1 H H CH₃ bond meta OCH₃ (parato OCHF₂) 572. 1 H H CH₃ bond meta CH₃ (para to X) 573. 1 CH₃ H CH₃ bondortho H 574. 1 CH₃ H CH₃ bond meta H 575. 1 CH₃ H CH₃ bond para H 576. 1CH₃ H CH₃ bond ortho CH₃ (para to X) 577. 1 CH₃ H CH₃ bond ortho CH₃(para to OCHF₂) 578. 1 CH₃ H CH₃ bond meta OCH₃ (para to X) 579. 1 CH₃ HCH₃ bond meta OCH₃ (para to OCHF₂) 580. 1 CH₃ H CH₃ bond meta CH₃ (parato X) 581. 2 H H CH₃ NH ortho H 582. 2 H H CH₃ NH meta H 583. 2 H H CH₃NH para H 584. 2 H H CH₃ NH ortho CH₃ (para to NH) 585. 2 H H CH₃ NHortho CH₃ (para to OCHF₂) 586. 2 H H CH₃ NH meta OCH₃ (para to NH) 587.2 H H CH₃ NH meta OCH₃ (para to OCHF₂) 588. 2 H H CH₃ NH meta CH₃ (parato NH) 589. 2 H H CH₃ NH ortho Cl (para to NH) 590. 2 H H CH₃ NH orthoCl (para to OCHF₂) 591. 2 H H CH₃ NH ortho F (para to NH) 592. 2 H H CH₃NH ortho F (para to OCHF₂) 593. 2 H H CH₃ NH meta OCHF₂ (para to NH)594. 2 CH₃ H CH₃ NH ortho H 595. 2 CH₃ H CH₃ NH meta H 596. 2 CH₃ H CH₃NH para H 597. 2 CH₃ H CH₃ NH ortho CH₃ (para to NH) 598. 2 CH₃ H CH₃ NHortho CH₃ (para to OCHF₂) 599. 2 CH₃ H CH₃ NH meta OCH₃ (para to NH)600. 2 CH₃ H CH₃ NH meta OCH₃ (para to OCHF₂) 601. 2 CH₃ H CH₃ NH metaCH₃ (para to NH) 602. 2 CH₃ H CH₃ NH ortho Cl (para to NH) 603. 2 CH₃ HCH₃ NH ortho Cl (para to OCHF₂) 604. 2 CH₃ H CH₃ NH ortho F (para to NH)605. 2 CH₃ H CH₃ NH ortho F (para to OCHF₂) 606. 2 CH₃ H CH₃ NH metaOCHF₂ (para to NH) 607. 2 H H CH₃ NCH₃ ortho H 608. 2 H H CH₃ NCH₃ metaH 609. 2 H H CH₃ NCH₃ para H 610. 2 H H CH₃ NCH₃ ortho CH₃ (para to X)611. 2 H H CH₃ NCH₃ ortho CH₃ (para to OCHF₂) 612. 2 H H CH₃ NCH₃ metaOCH₃ (para to X) 613. 2 H H CH₃ NCH₃ meta OCH₃ (para to OCHF₂) 614. 2 HH CH₃ NCH₃ meta CH₃ (para to X) 615. 2 H H CH₃ NCH₃ ortho Cl (para to X)616. 2 H H CH₃ NCH₃ ortho Cl (para to OCHF₂) 617. 2 H H CH₃ NCH₃ ortho F(para to X) 618. 2 H H CH₃ NCH₃ ortho F (para to OCHF₂) 619. 2 H H CH₃NCH₃ meta OCHF₂ (para to X) 620. 2 CH₃ H CH₃ NCH₃ ortho H 621. 2 CH₃ HCH₃ NCH₃ meta H 622. 2 CH₃ H CH₃ NCH₃ para H 623. 2 CH₃ H CH₃ NCH₃ orthoCH₃ (para to X) 624. 2 CH₃ H CH₃ NCH₃ ortho CH₃ (para to OCHF₂) 625. 2CH₃ H CH₃ NCH₃ meta OCH₃ (para to X) 626. 2 CH₃ H CH₃ NCH₃ meta OCH₃(para to OCHF₂) 627. 2 CH₃ H CH₃ NCH₃ meta CH₃ (para to X) 628. 2 CH₃ HCH₃ NCH₃ ortho Cl (para to X) 629. 2 CH₃ H CH₃ NCH₃ ortho Cl (para toOCHF₂) 630. 2 CH₃ H CH₃ NCH₃ ortho F (para to X) 631. 2 CH₃ H CH₃ NCH₃ortho F (para to OCHF₂) 632. 2 CH₃ H CH₃ NCH₃ meta OCHF₂ (para to X)633. 2 H H CH₃ NCH₂CH₃ ortho H 634. 2 H H CH₃ NCH₂CH₃ meta H 635. 2 H HCH₃ NCH₂CH₃ para H 636. 2 H H CH₃ NCH₂CH₃ ortho CH₃ (para to X) 637. 2 HH CH₃ NCH₂CH₃ ortho CH₃ (para to OCHF₂) 638. 2 H H CH₃ NCH₂CH₃ meta OCH₃(para to X) 639. 2 H H CH₃ NCH₂CH₃ meta OCH₃ (para to OCHF₂) 640. 2 H HCH₃ NCH₂CH₃ meta CH₃ (para to X) 641. 2 CH₃ H CH₃ NCH₂CH₃ ortho H 642. 2CH₃ H CH₃ NCH₂CH₃ meta H 643. 2 CH₃ H CH₃ NCH₂CH₃ para H 644. 2 CH₃ HCH₃ NCH₂CH₃ ortho CH₃ (para to X) 645. 2 CH₃ H CH₃ NCH₂CH₃ ortho CH₃(para to OCHF₂) 646. 2 CH₃ H CH₃ NCH₂CH₃ meta OCH₃ (para to X) 647. 2CH₃ H CH₃ NCH₂CH₃ meta OCH₃ (para to OCHF₂) 648. 2 CH₃ H CH₃ NCH₂CH₃meta CH₃ (para to X) 649. 2 H H CH₃ N(CH₂)₂CH₃ ortho H 650. 2 H H CH₃N(CH₂)₂CH₃ meta H 651. 2 H H CH₃ N(CH₂)₂CH₃ para H 652. 2 H H CH₃N(CH₂)₂CH₃ ortho CH₃ (para to X) 653. 2 H H CH₃ N(CH₂)₂CH₃ ortho CH₃(para to OCHF₂) 654. 2 H H CH₃ N(CH₂)₂CH₃ meta OCH₃ (para to X) 655. 2 HH CH₃ N(CH₂)₂CH₃ meta OCH₃ (para to OCHF₂) 656. 2 H H CH₃ N(CH₂)₂CH₃meta CH₃ (para to X) 657. 2 CH₃ H CH₃ N(CH₂)₂CH₃ ortho H 658. 2 CH₃ HCH₃ N(CH₂)₂CH₃ meta H 659. 2 CH₃ H CH₃ N(CH₂)₂CH₃ para H 660. 2 CH₃ HCH₃ N(CH₂)₂CH₃ ortho CH₃ (para to X) 661. 2 CH₃ H CH₃ N(CH₂)₂CH₃ orthoCH₃ (para to OCHF₂) 662. 2 CH₃ H CH₃ N(CH₂)₂CH₃ meta OCH₃ (para to X)663. 2 CH₃ H CH₃ N(CH₂)₂CH₃ meta OCH₃ (para to OCHF₂) 664. 2 CH₃ H CH₃N(CH₂)₂CH₃ meta CH₃ (para to X) 665. 2 H H CH₃ N(CH₂)-cyclopropyl orthoH 666. 2 H H CH₃ N(CH₂)-cyclopropyl meta H 667. 2 H H CH₃N(CH₂)-cyclopropyl para H 668. 2 H H CH₃ N(CH₂)-cyclopropyl ortho CH₃(para to X) 669. 2 H H CH₃ N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂)670. 2 H H CH₃ N(CH₂)-cyclopropyl meta OCH₃ (para to X) 671. 2 H H CH₃N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 672. 2 H H CH₃N(CH₂)-cyclopropyl meta CH₃ (para to X) 673. 2 CH₃ H CH₃N(CH₂)-cyclopropyl ortho H 674. 2 CH₃ H CH₃ N(CH₂)-cyclopropyl meta H675. 2 CH₃ H CH₃ N(CH₂)-cyclopropyl para H 676. 2 CH₃ H CH₃N(CH₂)-cyclopropyl ortho CH₃ (para to X) 677. 2 CH₃ H CH₃N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 678. 2 CH₃ H CH₃N(CH₂)-cyclopropyl meta OCH₃ (para to X) 679. 2 CH₃ H CH₃N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 680. 2 CH₃ H CH₃N(CH₂)-cyclopropyl meta CH₃ (para to X) 681. 2 H H CH₃ bond ortho H 682.2 H H CH₃ bond meta H 683. 2 H H CH₃ bond para H 684. 2 H H CH₃ bondortho CH₃ (para to X) 685. 2 H H CH₃ bond ortho CH₃ (para to OCHF₂) 686.2 H H CH₃ bond meta OCH₃ (para to X) 687. 2 H H CH₃ bond meta OCH₃ (parato OCHF₂) 688. 2 H H CH₃ bond meta CH₃ (para to X) 689. 2 CH₃ H CH₃ bondortho H 690. 2 CH₃ H CH₃ bond meta H 691. 2 CH₃ H CH₃ bond para H 692. 2CH₃ H CH₃ bond ortho CH₃ (para to X) 693. 2 CH₃ H CH₃ bond ortho CH₃(para to OCHF₂) 694. 2 CH₃ H CH₃ bond meta OCH₃ (para to X) 695. 2 CH₃ HCH₃ bond meta OCH₃ (para to OCHF₂) 696. 2 CH₃ H CH₃ bond meta CH₃ (parato X) 697. 1 H H F NH ortho H 698. 1 H H F NH meta H 699. 1 H H F NHpara H 700. 1 H H F NH ortho CH₃ (para to NH) 701. 1 H H F NH ortho CH₃(para to OCHF₂) 702. 1 H H F NH meta OCH₃ (para to NH) 703. 1 H H F NHmeta OCH₃ (para to OCHF₂) 704. 1 H H F NH meta CH₃ (para to NH) 705. 1 HH F NH ortho Cl (para to NH) 706. 1 H H F NH ortho Cl (para to OCHF₂)707. 1 H H F NH ortho F (para to NH) 708. 1 H H F NH ortho F (para toOCHF₂) 709. 1 H H F NH meta OCHF₂ (para to NH) 710. 1 CH₃ H F NH ortho H711. 1 CH₃ H F NH meta H 712. 1 CH₃ H F NH para H 713. 1 CH₃ H F NHortho CH₃ (para to NH) 714. 1 CH₃ H F NH ortho CH₃ (para to OCHF₂) 715.1 CH₃ H F NH meta OCH₃ (para to NH) 716. 1 CH₃ H F NH meta OCH₃ (para toOCHF₂) 717. 1 CH₃ H F NH meta CH₃ (para to NH) 718. 1 CH₃ H F NH orthoCl (para to NH) 719. 1 CH₃ H F NH ortho Cl (para to OCHF₂) 720. 1 CH₃ HF NH ortho F (para to NH) 721. 1 CH₃ H F NH ortho F (para to OCHF₂) 722.1 CH₃ H F NH meta OCHF₂ (para to NH) 723. 1 H H F NCH₃ ortho H 724. 1 HH F NCH₃ meta H 725. 1 H H F NCH₃ para H 726. 1 H H F NCH₃ ortho CH₃(para to X) 727. 1 H H F NCH₃ ortho CH₃ (para to OCHF₂) 728. 1 H H FNCH₃ meta OCH₃ (para to X) 729. 1 H H F NCH₃ meta OCH₃ (para to OCHF₂)730. 1 H H F NCH₃ meta CH₃ (para to X) 731. 1 H H F NCH₃ ortho Cl (parato X) 732. 1 H H F NCH₃ ortho Cl (para to OCHF₂) 733. 1 H H F NCH₃ orthoF (para to X) 734. 1 H H F NCH₃ ortho F (para to OCHF₂) 735. 1 H H FNCH₃ meta OCHF₂ (para to X) 736. 1 CH₃ H F NCH₃ ortho H 737. 1 CH₃ H FNCH₃ meta H 738. 1 CH₃ H F NCH₃ para H 739. 1 CH₃ H F NCH₃ ortho CH₃(para to X) 740. 1 CH₃ H F NCH₃ ortho CH₃ (para to OCHF₂) 741. 1 CH₃ H FNCH₃ meta OCH₃ (para to X) 742. 1 CH₃ H F NCH₃ meta OCH₃ (para to OCHF₂)743. 1 CH₃ H F NCH₃ meta CH₃ (para to X) 744. 1 CH₃ H F NCH₃ ortho Cl(para to X) 745. 1 CH₃ H F NCH₃ ortho Cl (para to OCHF₂) 746. 1 CH₃ H FNCH₃ ortho F (para to X) 747. 1 CH₃ H F NCH₃ ortho F (para to OCHF₂)748. 1 CH₃ H F NCH₃ meta OCHF₂ (para to X) 749. 1 H H F NCH₂CH₃ ortho H750. 1 H H F NCH₂CH₃ meta H 751. 1 H H F NCH₂CH₃ para H 752. 1 H H FNCH₂CH₃ ortho CH₃ (para to X) 753. 1 H H F NCH₂CH₃ ortho CH₃ (para toOCHF₂) 754. 1 H H F NCH₂CH₃ meta OCH₃ (para to X) 755. 1 H H F NCH₂CH₃meta OCH₃ (para to OCHF₂) 756. 1 H H F NCH₂CH₃ meta CH₃ (para to X) 757.1 CH₃ H F NCH₂CH₃ ortho H 758. 1 CH₃ H F NCH₂CH₃ meta H 759. 1 CH₃ H FNCH₂CH₃ para H 760. 1 CH₃ H F NCH₂CH₃ ortho CH₃ (para to X) 761. 1 CH₃ HF NCH₂CH₃ ortho CH₃ (para to OCHF₂) 762. 1 CH₃ H F NCH₂CH₃ meta OCH₃(para to X) 763. 1 CH₃ H F NCH₂CH₃ meta OCH₃ (para to OCHF₂) 764. 1 CH₃H F NCH₂CH₃ meta CH₃ (para to X) 765. 1 H H F N(CH₂)₂CH₃ ortho H 766. 1H H F N(CH₂)₂CH₃ meta H 767. 1 H H F N(CH₂)₂CH₃ para H 768. 1 H H FN(CH₂)₂CH₃ ortho CH₃ (para to X) 769. 1 H H F N(CH₂)₂CH₃ ortho CH₃ (parato OCHF₂) 770. 1 H H F N(CH₂)₂CH₃ meta OCH₃ (para to X) 771. 1 H H FN(CH₂)₂CH₃ meta OCH₃ (para to OCHF₂) 772. 1 H H F N(CH₂)₂CH₃ meta CH₃(para to X) 773. 1 CH₃ H F N(CH₂)₂CH₃ ortho H 774. 1 CH₃ H F N(CH₂)₂CH₃meta H 775. 1 CH₃ H F N(CH₂)₂CH₃ para H 776. 1 CH₃ H F N(CH₂)₂CH₃ orthoCH₃ (para to X) 777. 1 CH₃ H F N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 778.1 CH₃ H F N(CH₂)₂CH₃ meta OCH₃ (para to X) 779. 1 CH₃ H F N(CH₂)₂CH₃meta OCH₃ (para to OCHF₂) 780. 1 CH₃ H F N(CH₂)₂CH₃ meta CH₃ (para to X)781. 1 H H F N(CH₂)-cyclopropyl ortho H 782. 1 H H F N(CH₂)-cyclopropylmeta H 783. 1 H H F N(CH₂)-cyclopropyl para H 784. 1 H H FN(CH₂)-cyclopropyl ortho CH₃ (para to X) 785. 1 H H F N(CH₂)-cyclopropylortho CH₃ (para to OCHF₂) 786. 1 H H F N(CH₂)-cyclopropyl meta OCH₃(para to X) 787. 1 H H F N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂)788. 1 H H F N(CH₂)-cyclopropyl meta CH₃ (para to X) 789. 1 CH₃ H FN(CH₂)-cyclopropyl ortho H 790. 1 CH₃ H F N(CH₂)-cyclopropyl meta H 791.1 CH₃ H F N(CH₂)-cyclopropyl para H 792. 1 CH₃ H F N(CH₂)-cyclopropylortho CH₃ (para to X) 793. 1 CH₃ H F N(CH₂)-cyclopropyl ortho CH₃ (parato OCHF₂) 794. 1 CH₃ H F N(CH₂)-cyclopropyl meta OCH₃ (para to X) 795. 1CH₃ H F N(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 796. 1 CH₃ H FN(CH₂)-cyclopropyl meta CH₃ (para to X) 797. 1 H H F bond ortho H 798. 1H H F bond meta H 799. 1 H H F bond para H 800. 1 H H F bond ortho CH₃(para to X) 801. 1 H H F bond ortho CH₃ (para to OCHF₂) 802. 1 H H Fbond meta OCH₃ (para to X) 803. 1 H H F bond meta OCH₃ (para to OCHF₂)804. 1 H H F bond meta CH₃ (para to X) 805. 1 CH₃ H F bond ortho H 806.1 CH₃ H F bond meta H 807. 1 CH₃ H F bond para H 808. 1 CH₃ H F bondortho CH₃ (para to X) 809. 1 CH₃ H F bond ortho CH₃ (para to OCHF₂) 810.1 CH₃ H F bond meta OCH₃ (para to X) 811. 1 CH₃ H F bond meta OCH₃ (parato OCHF₂) 812. 1 CH₃ H F bond meta CH₃ (para to X) 813. 2 H H F NH orthoH 814. 2 H H F NH meta H 815. 2 H H F NH para H 816. 2 H H F NH orthoCH₃ (para to NH) 817. 2 H H F NH ortho CH₃ (para to OCHF₂) 818. 2 H H FNH meta OCH₃ (para to NH) 819. 2 H H F NH meta OCH₃ (para to OCHF₂) 820.2 H H F NH meta CH₃ (para to NH) 821. 2 H H F NH ortho Cl (para to NH)822. 2 H H F NH ortho Cl (para to OCHF₂) 823. 2 H H F NH ortho F (parato NH) 824. 2 H H F NH ortho F (para to OCHF₂) 825. 2 H H F NH metaOCHF₂ (para to NH) 826. 2 CH₃ H F NH ortho H 827. 2 CH₃ H F NH meta H828. 2 CH₃ H F NH para H 829. 2 CH₃ H F NH ortho CH₃ (para to NH) 830. 2CH₃ H F NH ortho CH₃ (para to OCHF₂) 831. 2 CH₃ H F NH meta OCH₃ (parato NH) 832. 2 CH₃ H F NH meta OCH₃ (para to OCHF₂) 833. 2 CH₃ H F NHmeta CH₃ (para to NH) 834. 2 CH₃ H F NH ortho Cl (para to NH) 835. 2 CH₃H F NH ortho Cl (para to OCHF₂) 836. 2 CH₃ H F NH ortho F (para to NH)837. 2 CH₃ H F NH ortho F (para to OCHF₂) 838. 2 CH₃ H F NH meta OCHF₂(para to NH) 839. 2 H H F NCH₃ ortho H 840. 2 H H F NCH₃ meta H 841. 2 HH F NCH₃ para H 842. 2 H H F NCH₃ ortho CH₃ (para to X) 843. 2 H H FNCH₃ ortho CH₃ (para to OCHF₂) 844. 2 H H F NCH₃ meta OCH₃ (para to X)845. 2 H H F NCH₃ meta OCH₃ (para to OCHF₂) 846. 2 H H F NCH₃ meta CH₃(para to X) 847. 2 H H F NCH₃ ortho Cl (para to X) 848. 2 H H F NCH₃ortho Cl (para to OCHF₂) 849. 2 H H F NCH₃ ortho F (para to X) 850. 2 HH F NCH₃ ortho F (para to OCHF₂) 851. 2 H H F NCH₃ meta OCHF₂ (para toX) 852. 2 CH₃ H F NCH₃ ortho H 853. 2 CH₃ H F NCH₃ meta H 854. 2 CH₃ H FNCH₃ para H 855. 2 CH₃ H F NCH₃ ortho CH₃ (para to X) 856. 2 CH₃ H FNCH₃ ortho CH₃ (para to OCHF₂) 857. 2 CH₃ H F NCH₃ meta OCH₃ (para to X)858. 2 CH₃ H F NCH₃ meta OCH₃ (para to OCHF₂) 859. 2 CH₃ H F NCH₃ metaCH₃ (para to X) 860. 2 CH₃ H F NH ortho Cl (para to X) 861. 2 CH₃ H F NHortho Cl (para to OCHF₂) 862. 2 CH₃ H F NH ortho F (para to X) 863. 2CH₃ H F NH ortho F (para to OCHF₂) 864. 2 CH₃ H F NH meta OCHF₂ (para toX) 865. 2 H H F NCH₂CH₃ ortho H 866. 2 H H F NCH₂CH₃ meta H 867. 2 H H FNCH₂CH₃ para H 868. 2 H H F NCH₂CH₃ ortho CH₃ (para to X) 869. 2 H H FNCH₂CH₃ ortho CH₃ (para to OCHF₂) 870. 2 H H F NCH₂CH₃ meta OCH₃ (parato X) 871. 2 H H F NCH₂CH₃ meta OCH₃ (para to OCHF₂) 872. 2 H H FNCH₂CH₃ meta CH₃ (para to X) 873. 2 CH₃ H F NCH₂CH₃ ortho H 874. 2 CH₃ HF NCH₂CH₃ meta H 875. 2 CH₃ H F NCH₂CH₃ para H 876. 2 CH₃ H F NCH₂CH₃ortho CH₃ (para to X) 877. 2 CH₃ H F NCH₂CH₃ ortho CH₃ (para to OCHF₂)878. 2 CH₃ H F NCH₂CH₃ meta OCH₃ (para to X) 879. 2 CH₃ H F NCH₂CH₃ metaOCH₃ (para to OCHF₂) 880. 2 CH₃ H F NCH₂CH₃ meta CH₃ (para to X) 881. 2H H F N(CH₂)₂CH₃ ortho H 882. 2 H H F N(CH₂)₂CH₃ meta H 883. 2 H H FN(CH₂)₂CH₃ para H 884. 2 H H F N(CH₂)₂CH₃ ortho CH₃ (para to X) 885. 2 HH F N(CH₂)₂CH₃ ortho CH₃ (para to OCHF₂) 886. 2 H H F N(CH₂)₂CH₃ metaOCH₃ (para to X) 887. 2 H H F N(CH₂)₂CH₃ meta OCH₃ (para to OCHF₂) 888.2 H H F N(CH₂)₂CH₃ meta CH₃ (para to X) 889. 2 CH₃ H F N(CH₂)₂CH₃ orthoH 890. 2 CH₃ H F N(CH₂)₂CH₃ meta H 891. 2 CH₃ H F N(CH₂)₂CH₃ para H 892.2 CH₃ H F N(CH₂)₂CH₃ ortho CH₃ (para to X) 893. 2 CH₃ H F N(CH₂)₂CH₃ortho CH₃ (para to OCHF₂) 894. 2 CH₃ H F N(CH₂)₂CH₃ meta OCH₃ (para toX) 895. 2 CH₃ H F N(CH₂)₂CH₃ meta OCH₃ (para to OCHF₂) 896. 2 CH₃ H FN(CH₂)₂CH₃ meta CH₃ (para to X) 897. 2 H H F N(CH₂)-cyclopropyl ortho H898. 2 H H F N(CH₂)-cyclopropyl meta H 899. 2 H H F N(CH₂)-cyclopropylpara H 900. 2 H H F N(CH₂)-cyclopropyl ortho CH₃ (para to X) 901. 2 H HF N(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 902. 2 H H FN(CH₂)-cyclopropyl Meta OCH₃ (para to X) 903. 2 H H F N(CH₂)-cyclopropylmeta OCH₃ (para to OCHF₂) 904. 2 H H F N(CH₂)-cyclopropyl meta CH₃ (parato X) 905. 2 CH₃ H F N(CH₂)-cyclopropyl ortho H 906. 2 CH₃ H FN(CH₂)-cyclopropyl meta H 907. 2 CH₃ H F N(CH₂)-cyclopropyl para H 908.2 CH₃ H F N(CH₂)-cyclopropyl ortho CH₃ (para to X) 909. 2 CH₃ H FN(CH₂)-cyclopropyl ortho CH₃ (para to OCHF₂) 910. 2 CH₃ H FN(CH₂)-cyclopropyl meta OCH₃ (para to X) 911. 2 CH₃ H FN(CH₂)-cyclopropyl meta OCH₃ (para to OCHF₂) 912. 2 CH₃ H FN(CH₂)-cyclopropyl meta CH₃ (para to X) 913. 2 H H F bond ortho H 914. 2H H F bond meta H 915. 2 H H F bond para H 916. 2 H H F bond ortho CH₃(para to X) 917. 2 H H F bond ortho CH₃ (para to OCHF₂) 918. 2 H H Fbond meta OCH₃ (para to X) 919. 2 H H F bond meta OCH₃ (para to OCHF₂)920. 2 H H F bond meta CH₃ (para to X) 921. 2 CH₃ H F bond ortho H 922.2 CH₃ H F bond meta H 923. 2 CH₃ H F bond para H 924. 2 CH₃ H F bondortho CH₃ (para to X) 925. 2 CH₃ H F bond ortho CH₃ (para to OCHF₂) 926.2 CH₃ H F bond meta OCH₃ (para to X) 927. 2 CH₃ H F bond meta OCH₃ (parato OCHF₂) 928. 2 CH₃ H F bond meta CH₃ (para to X) 929. 1 H H C₂H₅ NHortho H 930. 1 H H C₂H₅ NH meta H 931. 1 H H C₂H₅ NH para H 932. 1 H HC₂H₅ NH ortho CH₃ (para to NH) 933. 1 H H C₂H₅ NH ortho CH₃ (para toOCHF₂) 934. 1 H H C₂H₅ NH meta OCH₃ (para to NH) 935. 1 H H C₂H₅ NH metaOCH₃ (para to OCHF₂) 936. 1 H H C₂H₅ NH meta CH₃ (para to NH) 937. 1 H HC₂H₅ NH ortho Cl (para to NH) 938. 1 H H C₂H₅ NH ortho Cl (para toOCHF₂) 939. 1 H H C₂H₅ NH ortho F (para to NH) 940. 1 H H C₂H₅ NH orthoF (para to OCHF₂) 941. 1 H H C₂H₅ NH meta OCHF₂ (para to NH) 942. 1 CH₃H C₂H₅ NH ortho H 943. 1 CH₃ H C₂H₅ NH meta H 944. 1 CH₃ H C₂H₅ NH paraH 945. 1 CH₃ H C₂H₅ NH ortho CH₃ (para to NH) 946. 1 CH₃ H C₂H₅ NH orthoCH₃ (para to OCHF₂) 947. 1 CH₃ H C₂H₅ NH meta OCH₃ (para to NH) 948. 1CH₃ H C₂H₅ NH meta OCH₃ (para to OCHF₂) 949. 1 CH₃ H C₂H₅ NH meta CH₃(para to NH) 950. 1 CH₃ H C₂H₅ NH ortho Cl (para to NH) 951. 1 CH₃ HC₂H₅ NH ortho Cl (para to OCHF₂) 952. 1 CH₃ H C₂H₅ NH ortho F (para toNH) 953. 1 CH₃ H C₂H₅ NH ortho F (para to OCHF₂) 954. 1 CH₃ H C₂H₅ NHmeta OCHF₂ (para to NH) *Position of OCHF₂ versus X

Examples of compounds according to the present invention are thecompounds of the formula I′, their pharmacologically tolerated salts andthe N-oxides thereof, wherein R⁵ and R⁶ are hydrogen, and the meaningsof X, R¹, R², R³, R⁴ and n and the position of X is given in thefollowing table B:

TABLE B Position of X vs. difluoro- n R¹ R² R³ X dioxolan 955. 1 H HOCH₃ NH ortho 956. 1 H H OCH₃ NH meta 957. 1 CH₃ H OCH₃ NH ortho 958. 1CH₃ H OCH₃ NH meta 959. 2 H H OCH₃ NH ortho 960. 2 H H OCH₃ NH meta 961.2 CH₃ H OCH₃ NH ortho 962. 2 CH₃ H OCH₃ NH meta 963. 1 H H OCH₃ NCH₃ortho 964. 1 H H OCH₃ NCH₃ meta 965. 1 CH₃ H OCH₃ NCH₃ ortho 966. 1 CH₃H OCH₃ NCH₃ meta 967. 2 H H OCH₃ NCH₃ ortho 968. 2 H H OCH₃ NCH₃ meta969. 2 CH₃ H OCH₃ NCH₃ ortho 970. 2 CH₃ H OCH₃ NCH₃ meta 971. 1 H H OCH₃NCH₂CH₃ ortho 972. 1 H H OCH₃ NCH₂CH₃ meta 973. 1 CH₃ H OCH₃ NCH₂CH₃ortho 974. 1 CH₃ H OCH₃ NCH₂CH₃ meta 975. 2 H H OCH₃ NCH₂CH₃ ortho 976.2 H H OCH₃ NCH₂CH₃ meta 977. 2 CH₃ H OCH₃ NCH₂CH₃ ortho 978. 2 CH₃ HOCH₃ NCH₂CH₃ meta 979. 1 H H OCH₃ NCH₂CH₂CH₃ ortho 980. 1 H H OCH₃NCH₂CH₂CH₃ meta 981. 1 CH₃ H OCH₃ NCH₂CH₂CH₃ ortho 982. 1 CH₃ H OCH₃NCH₂CH₂CH₃ meta 983. 2 H H OCH₃ NCH₂CH₂CH₃ ortho 984. 2 H H OCH₃NCH₂CH₂CH₃ meta 985. 2 CH₃ H OCH₃ NCH₂CH₂CH₃ ortho 986. 2 CH₃ H OCH₃NCH₂CH₂CH₃ meta 987. 1 H H OCH₃ Bond meta 988. 1 CH₃ H OCH₃ Bond ortho989. 1 CH₃ H OCH₃ Bond meta 990. 2 H H OCH₃ Bond ortho 991. 2 H H OCH₃Bond meta 992. 2 CH₃ H OCH₃ Bond ortho 993. 2 CH₃ H OCH₃ Bond meta 994.1 H H OCHF₂ NCH₃ ortho 995. 1 H H OCHF₂ NCH₃ meta 996. 1 CH₃ H OCHF₂NCH₃ ortho 997. 1 CH₃ H OCHF₂ NCH₃ meta 998. 2 H H OCHF₂ NCH₃ ortho 999.2 H H OCHF₂ NCH₃ meta 1000. 2 CH₃ H OCHF₂ NCH₃ ortho 1001. 2 CH₃ H OCHF₂NCH₃ meta 1002. 1 H H OCHF₂ NCH₂CH₃ ortho 1003. 1 H H OCHF₂ NCH₂CH₃ meta1004. 1 CH₃ H OCHF₂ NCH₂CH₃ ortho 1005. 1 CH₃ H OCHF₂ NCH₂CH₃ meta 1006.2 H H OCHF₂ NCH₂CH₃ ortho 1007. 2 H H OCHF₂ NCH₂CH₃ meta 1008. 2 CH₃ HOCHF₂ NCH₂CH₃ ortho 1009. 2 CH₃ H OCHF₂ NCH₂CH₃ meta 1010. 1 H H OCHF₂NCH₂CH₂CH₃ ortho 1011. 1 H H OCHF₂ NCH₂CH₂CH₃ meta 1012. 1 CH₃ H OCHF₂NCH₂CH₂CH₃ ortho 1013. 1 CH₃ H OCHF₂ NCH₂CH₂CH₃ meta 1014. 2 H H OCHF₂NCH₂CH₂CH₃ ortho 1015. 2 H H OCHF₂ NCH₂CH₂CH₃ meta 1016. 2 CH₃ H OCHF₂NCH₂CH₂CH₃ ortho 1017. 2 CH₃ H OCHF₂ NCH₂CH₂CH₃ meta 1018. 1 H H OCHF₂Bond meta 1019. 1 CH₃ H OCHF₂ Bond ortho 1020. 1 CH₃ H OCHF₂ Bond meta1021. 2 H H OCHF₂ Bond ortho 1022. 2 H H OCHF₂ Bond meta 1023. 2 CH₃ HOCHF₂ Bond ortho 1024. 2 CH₃ H OCHF₂ Bond meta 1025. 1 H H CH₃ NCH₃ortho 1026. 1 H H CH₃ NCH₃ meta 1027. 1 CH₃ H CH₃ NCH₃ ortho 1028. 1 CH₃H CH₃ NCH₃ meta 1029. 2 H H CH₃ NCH₃ ortho 1030. 2 H H CH₃ NCH₃ meta1031. 2 CH₃ H CH₃ NCH₃ ortho 1032. 2 CH₃ H CH₃ NCH₃ meta 1033. 1 H H CH₃NCH₂CH₃ ortho 1034. 1 H H CH₃ NCH₂CH₃ meta 1035. 1 CH₃ H CH₃ NCH₂CH₃ortho 1036. 1 CH₃ H CH₃ NCH₂CH₃ meta 1037. 2 H H CH₃ NCH₂CH₃ ortho 1038.2 H H CH₃ NCH₂CH₃ meta 1039. 2 CH₃ H CH₃ NCH₂CH₃ ortho 1040. 2 CH₃ H CH₃NCH₂CH₃ meta 1041. 1 H H CH₃ NCH₂CH₂CH₃ ortho 1042. 1 H H CH₃ NCH₂CH₂CH₃meta 1043. 1 CH₃ H CH₃ NCH₂CH₂CH₃ ortho 1044. 1 CH₃ H CH₃ NCH₂CH₂CH₃meta 1045. 2 H H CH₃ NCH₂CH₂CH₃ ortho 1046. 2 H H CH₃ NCH₂CH₂CH₃ meta1047. 2 CH₃ H CH₃ NCH₂CH₂CH₃ ortho 1048. 2 CH₃ H CH₃ NCH₂CH₂CH₃ meta1049. 1 H H CH₃ Bond meta 1050. 1 CH₃ H CH₃ Bond ortho 1051. 1 CH₃ H CH₃Bond meta 1052. 2 H H CH₃ Bond ortho 1053. 2 H H CH₃ Bond meta 1054. 2CH₃ H CH₃ Bond ortho 1055. 2 CH₃ H CH₃ Bond meta 1056. 1 H H F NCH₃ortho 1057. 1 H H F NCH₃ meta 1058. 1 CH₃ H F NCH₃ ortho 1059. 1 CH₃ H FNCH₃ meta 1060. 2 H H F NCH₃ ortho 1061. 2 H H F NCH₃ meta 1062. 2 CH₃ HF NCH₃ ortho 1063. 2 CH₃ H F NCH₃ meta 1064. 1 H H F NCH₂CH₃ ortho 1065.1 H H F NCH₂CH₃ meta 1066. 1 CH₃ H F NCH₂CH₃ ortho 1067. 1 CH₃ H FNCH₂CH₃ meta 1068. 2 H H F NCH₂CH₃ ortho 1069. 2 H H F NCH₂CH₃ meta1070. 2 CH₃ H F NCH₂CH₃ ortho 1071. 2 CH₃ H F NCH₂CH₃ meta 1072. 1 H H FNCH₂CH₂CH₃ ortho 1073. 1 H H F NCH₂CH₂CH₃ meta 1074. 1 CH₃ H FNCH₂CH₂CH₃ ortho 1075. 1 CH₃ H F NCH₂CH₂CH₃ meta 1076. 2 H H FNCH₂CH₂CH₃ ortho 1077. 2 H H F NCH₂CH₂CH₃ meta 1078. 2 CH₃ H FNCH₂CH₂CH₃ ortho 1079. 2 CH₃ H F NCH₂CH₂CH₃ meta 1080. 1 H H F Bond meta1081. 1 CH₃ H F Bond ortho 1082. 1 CH₃ H F Bond meta 1083. 2 H H F Bondortho 1084. 2 H H F Bond meta 1085. 2 CH₃ H F Bond ortho 1086. 2 CH₃ H FBond meta

Table C:

Further examples are compounds of the formula I, where R⁶ is hydrogen,n, R¹, R³, X and R⁵ are as defined in the rows of Table A, wherein R² ismethyl instead of hydrogen (compounds 1061 to 1988) and thephysiologically tolerated acid addition salts or the N-oxides thereof.

Table D:

Further examples are compounds of the formula I′, where R⁵ and R⁶ arehydrogen, n, R¹, R³ and X are as defined in the rows of Table B, whereinR² is methyl instead of hydrogen (compounds 1989 to 2120) and thephysiologically tolerated acid addition salts or the N-oxides thereof.

The compounds I and I′according to the invention are prepared in analogywith methods known from the literature. An important approach to thecompounds according to the invention is offered by the reaction of a1-(piperazin-1-yl) or 1-(homopiperazin-1-yl) compound II where R³ ise.g. methyl or methoxy with chlorosulfonic acid and subsequent reactionof the intermediate sulfonyl chloride with an aniline derivative IV asdepicted in scheme 1 or with a 2,2-difluorobenzo[1,3]dioxolanederivative IVa as depicted in scheme 1a.

In schemes 1 and 1a, n, R² and R³ are as defined herein. R^(a) is anitrogen protecting group or methyl. Suitable N-protecting groups aredescribed, for example, in P. J. Kocienski “Protecting Groups”, 2^(nd)ed., Georg Thieme Verlag, Stuttgart 2000, pp 186-237 and in theliterature cited therein. Preferred examples of N-protecting groups aree.g. oxycarbonyl groups such as C₁-C₆-alkoxycarbonyl, e.g.methoxycarbonyl, ethoxycarbonyl and Boc (tert-butoxycarbonyl) and otheroxycarbonyl groups such as benzyloxycarbonyl (Cbz), allyloxycarbonyl,9-fluorenylmethoxycarbonyl (Fmoc) and 2-trimethylsilylethoxycarbonyl(Teoc), or 2-propenyl (allyl). Especially preferred for introduction ofa sulfonylchloride group is the trifluoroacetyl group as a protectinggroup for the piperazine or homopiperazine nitrogen. X¹ is anucleophilically displaceable leaving group, in particular a halogenatom and, especially, chlorine or bromine.

Sulfone compounds of the present invention where X is a bond can beprepared according to schemes 2 and 3, either from compounds VII (whichin itself can be prepared from aniline compounds VI where the NH₂ groupis transformed into a group X² which can either be e.g. iodine orbromine, via a Sandmeyer reaction) by reaction with a thiophenolcompound VIIIa and subsequent oxidation of the sulfide (scheme 2) withsuitable oxidizing agents such as oxone or peracids, or by reaction of acompound VII with the salt of a sulfinic acid derivative VIIIb (usuallythe sodium salt) without the further need for an oxidative step (scheme3; e.g. Synlett, 2003, 361 Cacchi et al.).

In schemes 2 and 3, n, R² and R³ are as defined herein. R^(a) is anitrogen protecting group or methyl.

Compounds of formula (IX) can be prepared by the palladium-catalyzedreaction of the sulfinic acid salt VII Ib with compounds VII, wherein X²is bromine or iodine. A suitable palladium catalyst istris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃). The sulfone (IX)is usually prepared in the presence of Xantphos, a rigid bidendateligand. The reaction is also usually carried out in the presence ofn-tetrabutylammonium chloride. Sulfinate compounds VIIIb are eithercommercially available or can e.g. be prepared from the correspondingsulfonyl chlorides by reaction with sodium sulfite under basicconditions.

Compounds VIIa, wherein R³ is as defined above, can also be preparedfrom suitable aniline compounds by reaction with a suitably protectedbis(2-chloroethyl)-amine where R^(a) can e.g. be the p-tolyl-sulfonylgroup.

Compounds of the formulae V and Va, wherein R^(a) is a nitrogenprotecting group, in particular trifluoroacetyl, a C₁-C₆-alkoxycarbonylgroup such as methoxycarbonyl, ethoxycarbonyl and Boc(tert-butoxycarbonyl), are novel and thus form also part of the presentinvention.

Compounds of the formula V, wherein R^(a) is methyl correspond tocompounds I, wherein R¹ is methyl. Compounds of the formula Va, whereinR^(a) is methyl correspond to compounds I′, wherein R¹ is methyl.

The reaction depicted in schemes 1 and 1a takes place under the reactionconditions which are customary for preparing arylsulfonamide compoundsor arylsulfonic esters, respectively, and which are described, forexample, in J. March, Advanced Organic Chemistry, 3^(rd) edition, JohnWiley & Sons, New York, 1985 p 444 and the literature cited therein,European J. Org. Chem. 2002 (13), pp. 2094-2108, Tetrahedron 2001, 57(27) pp. 5885-5895, Bioorganic and Medicinal Chemistry Letters, 2000,10(8), pp. 835-838 and Synthesis 2000 (1), pp. 103-108.

The reaction customarily takes place in an inert solvent, for example inan ether, such as diethyl ether, diisopropyl ether, methyl tert-butylether or tetrahydrofuran, a halohydrocarbon, such as dichloromethane, analiphatic or cycloaliphatic hydrocarbon, such as pentane, hexane orcyclohexane, or an aromatic hydrocarbon, such as toluene, xylene, cumeneand the like, or in a mixture of the abovementioned solvents. Thereaction of compound III with compound IV (or compound IVa) iscustomarily carried out in the presence of an auxiliary base. Suitablebases are inorganic bases, such as sodium carbonate or potassiumcarbonate, or sodium hydrogen carbonate or potassium hydrogen carbonate,and organic bases, for example trialkylamines, such as triethylamine, orpyridine compounds, such as pyridine, lutidine, 4-dimethylamino-pyridineand the like. The latter compounds can at the same time serve assolvents. The auxiliary base is customarily employed in at leastequimolar quantities, based on the amine compound II.

The reaction of compound III with compound IV or IVa, respectivelyyields compound V or Va, respectively, which, in case R^(a) is anN-protecting group, is deprotected to yield the compound of the generalformula I or I′, wherein R¹ is hydrogen. Deprotection of the compound Vor Va, respectively, can be achieved by standard methods, e.g. by themethods as described in P. J. Kocienski “Protecting Groups”, 2^(nd) ed.,Georg Thieme Verlag, Stuttgart 2000, pp 186-237 and in the literaturecited therein.

Customary methods can then be used to react these compounds with amethylating agent such as methyl iodide or dimethyl sulfate resulting ina compound of the formula I or I′, respectively, in which R¹ is methyl.The reaction conditions which are required for this methylating reactionare disclosed, for example, in WO 02/083652, Tetrahedron 2000, 56(38)pp. 7553-7560 and Synlett. 2000 (4), pp. 475-480.

For preparing a compound of formula I or I′, respectively, in which R¹is methyl, it is likewise possible to react a compound of formula I orI′, in which R¹ is hydrogen, with formaldehyde in the presence of areducing agent in a sense of a reductive amination. Suitable reducingagents are borohydrides such as sodium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride or borane-pyridine. Thereductive amination is usually carried out in an organic solvent such asdichloromethane, 1,2-dichloroethane, tetrahydrofuran or acetonitrile.

Reaction of the compound V or Va with an alkylating agent yields acompound of the formula V′ or V′a, respectively, wherein n, R^(a), R²and R³ are as defined above. In the compound of the formula V′ or V′a,respectively, the sulfonamide hydrogen is replaced by C₁-C₄ alkyl, C₃-C₄cycloalkyl, or C₃-C₄ cycloalkyl-CH₂—.

It is possible to react the compound V or Va with a methylating agentsuch as methyl iodide or dimethyl sulfate to yield a compound of theformula Vc or Vd, respectively, wherein n, R^(a), R² and R³ are asdefined above.

If R^(a) in formulae Vc or Vd is an N-protecting group, compound Vc orVd, respectively is deprotected to yield the compound of the generalformula I, wherein R¹ is hydrogen. Deprotection of the compound Vc or Vdcan be achieved by standard methods, e.g. by the methods as described inP. J. Kocienski “Protecting Groups”, 2^(nd) ed., Georg Thieme Verlag,Stuttgart 2000, pp 186-237 and in the literature cited therein.

Compounds V and IX where R^(a) is methyl can best be prepared byreaction of compounds V and IX where R^(a) is hydrogen with formaldehydeunder reducing conditions as described above.

The compounds of the general formula VI are known per se or can beprepared in the manner shown in scheme 4.

In scheme 4, n, R^(a), R² and R³ are as defined herein.

In step i) of scheme 4, the compound X is subjected to a nitration understandard conditions thereby yielding compound XI. Reaction conditionscan be taken e.g. from U.S. Pat. No. 6,599,904 or from the workingexamples of the present application.

In step ii) of scheme 4, the NH-group of compound XI is protected,either by a conventional N-protecting group as defined above or byintroducing a methyl group via a methylating agent such as methylbromide, methyl iodide or dimethyl sulfate. Introduction of anN-protecting group into compound XI can be achieved by standard methods,e.g. by the methods as described in P. J. Kocienski “Protecting Groups”,2nd ed., Georg Thieme Verlag, Stuttgart 2000, pp 186-237 and in theliterature cited therein. Methylation of compound XI is likewiseachieved by standard methods of Organic chemistry.

In step iii), the nitro group in compound XII is reduced to the NH₂group to yield compound VI. The reaction conditions which are requiredfor step iii) correspond to the customary conditions for reducingaromatic nitro groups which have been described extensively in theliterature (see, for example, J. March, Advanced Organic Chemistry, 3rded., J. Wiley & Sons, New-York, 1985, p. 1183 and the literature citedin this reference). The reduction can be achieved, for example, byreacting the nitro compound XII with a metal such as iron, zinc or tinunder acidic reaction conditions, i.e. using nascent hydrogen, or usinga complex hydride such as lithium aluminum hydride or sodiumborohydride, preferably in the presence of transition metal compounds ofnickel or cobalt such as NiCl₂(P(phenyl)₃)₂, or CoCl₂, (see Ono et al.Chem. Ind. (London), 1983 p. 480), or using NaBH₂S₃ (see Lalancette etal. Can. J. Chem. 49, 1971, p. 2990), with it being possible to carryout these reductions, depending on the given reagent, in substance or ina solvent or diluent. Alternatively, the reduction of XII to VI can becarried out with hydrogen in the presence of a transition metalcatalyst, e.g. using hydrogen in the presence of catalysts based onplatinum, palladium, nickel, ruthenium or rhodium. The catalysts cancontain the transition metal in elemental form or in the form of acomplex compound, of a salt or of an oxide of the transition metal, withit being possible, for the purpose of modifying the activity, to usecustomary coligands, e.g. organic phosphine compounds, such astriphenylphosphine, tricyclohexylphosphine or tri-n-butylphosphines orphosphites. The catalyst is customarily employed in quantities of from0.001 to 1 mol per mol of compound XII, calculated as catalyst metal. Ina preferred variant, the reduction is effected using tin(II) chloride inanalogy with the methods described in Bioorganic and Medicinal ChemistryLetters, 2002, 12(15), pp. 1917-1919 and J. Med. Chem. 2002, 45(21), pp.4679-4688. The reaction of XII with tin(II) chloride is preferablycarried out in an inert organic solvent, preferably an alcohol such asmethanol, ethanol, isopropanol or butanol.

If not indicated otherwise, the above-described reactions are generallycarried out in a solvent at temperatures between room temperature andthe boiling temperature of the solvent employed. Alternatively, theactivation energy which is required for the reaction can be introducedinto the reaction mixture using microwaves, something which has provedto be of value, in particular, in the case of the reactions catalyzed bytransition metals (with regard to reactions using microwaves, seeTetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a generalmanner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH2002.

The acid addition salts of compounds I and I′ are prepared in acustomary manner by mixing the free base with a corresponding acid,where appropriate in solution in an organic solvent, for exampleacetonitrile, a lower alcohol, such as methanol, ethanol or propanol, anether, such as diethyl ether, methyl tert-butyl ether or diisopropylether, a ketone, such as acetone or methyl ethyl ketone, an ester, suchas ethyl acetate, mixtures thereof as well as mixtures thereof withwater.

The compounds of the present invention can be a 5-HT₆ receptor agonist,including partial agonistic activity, or a 5-HT₆ receptor antagonist,including inverse agonist activity.

The compounds of formulae I and I′according to the present invention, aswell as their salts and their N-oxides, have a surprisingly highaffinity for 5-HT₆ receptors. The high affinity of the compoundsaccording to the invention for 5-HT₆ receptors is reflected in very lowin-vitro receptor binding constants (K_(i)(5-HT₆) values) of as a ruleless than 500, 100 or 50 nM (nmol/l), preferably of less than 10 nM and,in particular of less than 5 nM. The displacement of ³H-LSD can, forexample, be used in receptor binding studies for determining bindingaffinities to 5-HT₆ receptors.

Furthermore the compounds of formulae I and I′, as well as their saltsand their N-oxides, are highly selective 5-HT₆ receptor ligands which,because of their low affinity for other receptors such as dopaminereceptors, adrenergic receptors, muscarinic receptors, histaminereceptors, opiate receptors, in particular dopamine D₂, α₁-adrenergicand histamine H₁ receptors, give rise to fewer side-effects than other,less selective 5-HT₆ ligands.

For instance the 5-HT₆/D₂, 5-HT₆/α₁-adrenergic or 5-HT₆/H₁ selectivitiesof the compounds according to the present invention, i.e. the ratiosK_(i)(D₂)/K_(i)(5-HT₆), K_(i)(α₁-adrenergic)/K_(i)(5-HT₆) orK_(i)(H₁)/K_(i)(5-HT₆) of the receptor binding constants, is as a ruleat least 25, preferably at least 50, even better at least 100.

The displacement of [³H]SCH23390 or [¹²⁵I]spiperone can be used, forexample, for carrying out receptor binding studies on D₁, D₂ and D₄receptors.

Furthermore the compounds of the present invention because of theirstructural features are susceptible to display an enhanced brainpenetration than other known 5-HT₆ receptor ligands.

Because of their binding profile, the compounds of the present inventioncan be used for treating diseases which respond to 5-HT₆ receptorligands (or which are susceptible to treatment with a 5-HT₆ receptorligand), i.e. they are effective for treating those medical disorders ordiseases in which exerting an influence on (modulating) the 5-HT₆receptors leads to an improvement in the clinical picture or to thedisease being cured. Examples of these diseases are disorders ordiseases of the central nervous system.

Disorders or diseases of the central nervous system are understood asmeaning disorders which affect the spinal cord and, in particular, thebrain. Within the meaning of the invention, the term “disorder” denotesdisturbances and/or anomalies which are as a rule regarded as beingpathological conditions or functions and which can manifest themselvesin the form of particular signs, symptoms and/or malfunctions. While thetreatment according to the invention can be directed toward individualdisorders, i.e. anomalies or pathological conditions, it is alsopossible for several anomalies, which may be causatively linked to eachother, to be combined into patterns, i.e. syndromes, which can betreated in accordance with the invention.

The disorders which can be treated in accordance with the invention arein particular disorders which respond to a modulation of the 5-HT₆receptor. They include cognitive dysfunctions, such as a deficit inmemory, cognition and learning, in particular associated withAlzheimer's disease, age-related cognitive decline and mild cognitiveimpairment, attention deficit disorder/hyperactivity syndrome,personality disorders, such as schizophrenia, in particular cognitivedeficits related with schizophrenia, affective disorders such asdepression, anxiety and obsessive compulsive disorders, motion or motordisorders such as Parkinson's disease and epilepsy, migraine, sleepdisorders (including disturbances of the Circadian rhythm), feedingdisorders, such as anorexia and bulimia, certain gastrointestinaldisorders such as Irritable Bowel Syndrome, diseases associated withneurodegeneration, such as stroke, spinal or head trauma and headinjuries, such as hydrocephalus, addiction diseases including e.g. drugaddiction and obesity.

The addiction diseases include psychic disorders and behavioraldisturbances which are caused by the abuse of psychotropic substances,including certain pharmaceuticals, such as sedative, anxiolytica,hypnotics or narcotics (hereinafter also referred to as drug addiction),and also other addiction diseases, such as addiction to gaming(gambling; impulse control disorders not elsewhere classified). Examplesof addictive substances are: opioids (e.g. morphine, heroin andcodeine), cocaine; nicotine; alcohol; substances which interact with theGABA chloride channel complex, sedatives, hypnotics and tranquilizers,for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants,such as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamineand amphetamine-like substances such as methylphenidate and otherstimulants including caffeine. Addictive substances which comeparticularly into consideration are opioids, cocaine, amphetamine oramphetamine-like substances, hallucinogens, NMDA-receptor antagonistssuch phencyclidine and related cyclidines, dextrometorphan, dextrorphan,ibogaine, ketimine and tiletamine, cannabis, nicotine and alcohol. Otheraddiction diseases include gaming (gambling), including problem gambling(compulsive gambling, ludomania), computer or video game addiction andinternet addiction.

With regard to the treatment of addiction diseases, particularpreference is given to those compounds according to the presentinvention which themselves do not possess any psychotropic effect. Thiscan also be observed in a test using rats, which, after having beenadministered compounds which can be used in accordance with theinvention, reduce their self administration of psychotropic substances,for example cocaine or alcohol.

According to another aspect of the present invention, the compoundsaccording to the invention are suitable for treating disorders whosecauses can at least partially be attributed to an anomalous activity of5-HT₆ receptors.

According to another aspect of the present invention, the treatment isdirected, in particular, toward those disorders which can be influenced,within the sense of an expedient medicinal treatment, by the binding ofpreferably exogeneously administered binding partners (ligands) to 5-HT₆receptors.

The diseases which can be treated with the compounds according to theinvention are frequently characterized by progressive development, i.e.the above-described conditions change over the course of time; as arule, the severity increases and conditions may possibly merge into eachother or other conditions may appear in addition to those which alreadyexist.

The compounds of the present invention can be used to treat a largenumber of signs, symptoms and/or malfunctions which are connected withthe disorders of the central nervous system and, in particular, theabovementioned conditions. These signs, symptoms and/or malfunctionsinclude, for example, a disturbed relationship to reality, lack ofinsight and ability to meet customary social norms or the demands madeby life, changes in temperament, changes in individual drives, such ashunger, sleep, thirst, etc., and in mood, disturbances in the ability toobserve and combine, changes in personality, in particular emotionallability, hallucinations, ego-disturbances, distractedness, ambivalence,autism, depersonalization and false perceptions, delusional ideas,chanting speech, lack of synkinesia, short-step gait, flexed posture oftrunk and limbs, tremor, poverty of facial expression, monotonousspeech, depressions, apathy, impeded spontaneity and decisiveness,impoverished association ability, anxiety, nervous agitation,stammering, social phobia, panic disturbances, withdrawal symptoms inassociation with dependency, maniform syndromes, states of excitationand confusion, dysphoria, dyskinetic syndromes and tic disorders, e.g.Huntington's chorea and Gilles-de-la-Tourette's syndrome, vertigosyndromes, e.g. peripheral positional, rotational and oscillatoryvertigo, melancholia, hysteria, hypochondria and the like.

Within the meaning of the invention, a treatment also includes apreventive treatment (prophylaxis), in particular as relapse prophylaxisor phase prophylaxis, as well as the treatment of acute or chronicsigns, symptoms and/or malfunctions. The treatment can be orientatedsymptomatically, for example as the suppression of symptoms. It can beeffected over a short period, be orientated over the medium term or canbe a long-term treatment, for example within the context of amaintenance therapy.

The compounds according to the invention are preferentially suitable fortreating diseases of the central nervous system, more preferably fortreating cognitive dysfunctions and in particular, for treatingcognitive dysfunctions associated with schizophrenia or with Alzheimer'sdisease.

According to another aspect of the invention the compounds of thepresent invention are particularly suitable for treating addictiondiseases caused for instance by the abuse of psychotropic substances,such as pharmaceuticals, narcotics, nicotine or alcohol, includingpsychic disorders and behavioral disturbances related thereto. Thecompounds of the present invention are likewise particularly suitablefor treating addiction diseases which are not caused by the abuse ofpsychotropic substances, such as gaming (gambling), including problemgambling (compulsive gambling, ludomania), computer or video gameaddiction and internet addiction. With regard to addiction diseases, thecompound of the present invention can be used for the therapy duringaddiction and also for preventing relapse into addiction.

According to another aspect of the invention the compounds of formulae(I) and (I)′, their salts and their N-oxides are particularly suitablefor treating nutritional disorders, such as obesity, as well as diseasesrelated thereto, such as cardiovascular diseases, digestive diseases,respiratory diseases, cancer or type 2 diabetes.

Within the context of the treatment, the use according to the inventionof the described compounds involves a method. In this method, aneffective quantity of one or more compounds, as a rule formulated inaccordance with pharmaceutical and veterinary practice, is administeredto the individual to be treated, preferably a mammal, in particular ahuman being, productive animal or domestic animal. Whether such atreatment is indicated, and in which form it is to take place, dependson the individual case and is subject to medical assessment (diagnosis)which takes into consideration signs, symptoms and/or malfunctions whichare present, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeateddaily administration, where appropriate together, or alternating, withother active compounds or active compound-containing preparations suchthat a daily dose of preferably from about 0.1 to 1000 mg/kg ofbodyweight, in the case of oral administration, or of from about 0.1 to100 mg/kg of bodyweight, in the case of parenteral administration, issupplied to an individual to be treated.

The invention also relates to the production of pharmaceuticalcompositions for treating an individual, preferably a mammal, inparticular a human being, productive animal or domestic animal. Thus,the compounds of formulae I or I′, their salts and/or their N-oxides arecustomarily administered in the form of pharmaceutical compositionswhich comprise a pharmaceutically acceptable excipient together with atleast one compound according to the invention and, where appropriate,other active compounds. These compositions can, for example, beadministered orally, rectally, transdermally, subcutaneously,intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinalforms, such as powders, granules, tablets, in particular film tablets,lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hardgelatin capsules and soft gelatin capsules, suppositories or vaginalmedicinal forms, semisolid medicinal forms, such as ointments, creams,hydrogels, pastes or plasters, and also liquid medicinal forms, such assolutions, emulsions, in particular oil-in-water emulsions, suspensions,for example lotions, injection preparations and infusion preparations,and eyedrops and eardrops.

Implanted release devices can also be used for administering inhibitorsaccording to the invention. In addition, it is also possible to useliposomes or microspheres.

When producing the compositions, the compounds according to theinvention are optionally mixed or diluted with one or more excipients.Excipients can be solid, semisolid or liquid materials which serve asvehicles, carriers or medium for the active compound.

Suitable excipients are listed in the specialist medicinal monographs.In addition, the formulations can comprise pharmaceutically acceptablecarriers or customary auxiliary substances, such as glidants; wettingagents; emulsifying and suspending agents; preservatives; antioxidants;antiirritants; chelating agents; coating auxiliaries; emulsionstabilizers; film formers; gel formers; odor masking agents; tastecorrigents; resin; hydrocolloids; solvents; solubilizers; neutralizingagents; diffusion accelerators; pigments; quaternary ammonium compounds;refatting and overfatting agents; raw materials for ointments, creams oroils; silicone derivatives; spreading auxiliaries; stabilizers;sterilants; suppository bases; tablet auxiliaries, such as binders,fillers, glidants, disintegrants or coatings; propellants; dryingagents; opacifiers; thickeners; waxes; plasticizers and white mineraloils. A formulation in this regard is based on specialist knowledge asdescribed, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe fürPharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliarysubstances for pharmacy, cosmetics and related fields], 4^(th) edition,Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

The following examples serve to explain the present invention withoutlimiting its scope.

The compounds were either characterized via proton-NMR ind₆-dimethylsulfoxid or d-chloroform on a 400 MHz or 500 MHz NMRinstrument (Bruker AVANCE), or by mass spectrometry, generally recordedvia HPLC-MS in a fast gradient on C18-material (electrospray-ionisation(ESI) mode), or melting point.

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (δ) expressed in parts per million (ppm). The relativearea of the shifts in the ¹H NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated as singlet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet(t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet(m).

I. Preparation of the Intermediate Compounds V and IX I.1 Preparation ofthe Intermediate Compounds V Preparation Example 1N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonamide

1.1 2,2,2-Trifluoro-1-(4-o-tolyl-piperazin-1-yl)-ethanone

29.9 g of 2,2,2-trifluoroacetic anhydride (104 mmol) were dissolved in150 mL of dichloromethane, cooled to −20° C., and 20 g of1-o-tolylpiperazine-1,4-diium chloride (80 mmol)—dissolved in 150 mL ofdichloromethane—added dropwise. After stirring for 16 h at roomtemperature, 400 ml of ice water were added, the organic phaseseparated, washed twice with water, and the pH adjusted to neutral with1% aqueous sodium bicarbonate solution. The organic phase was washedwith saturated aqueous sodium chloride, dried over sodium sulphate,filtered and the solvent evaporated to yield 21.5 g of product whichcrystallized upon cooling.

1.24-Methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonylchloride

To a solution of 2 g of2,2,2-trifluoro-1-(4-o-tolyl-piperazin-1-yl)-ethanone (7.35 mmol) in 5mL of dichloromethane at −5° C. were slowly added 19.7 g ofchlorosulfonic acid (169 mmol). After stirring for 2 h at −5° C., thereaction mixture continued stirring for 16 h, thereby slowly allowed towarm to room temperature. After cooling to 0° C., the reaction mixturewas slowly added to a water/ice mixture. The aqueous phase was extractedfive times with dichloromethane, the combined organic phases washed withaqueous sodium bicarbonate solution and saturated sodium chloridesolution. The organic layer was dried over magnesium sulphate, filtered,and the solvent evaporated to yield 2.2 g of product as a white solid.

1.3N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonamide

0.429 g of 3-(difluoromethoxy)-aniline (2.7 mmol) were dissolved in 5 mLof pyridine. 1 g of4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonylchloride(2.7 mmol) were added slowly at room temperature. After stirring for 16h at room temperature, the reaction mixture was evaporated several timesafter addition of toluene. The residue was dissolved in dichloromethaneand washed several times with 5% aqueous ammonium chloride. The organicphase was then washed with saturated aqueous sodium chloride, dried oversodium sulphate, filtered, and the solvent evaporated. The crude productwas purified via silica gel chromatography usingdichloromethane/methanol (0-5%) to yield 0.63 g of product.

For the preparation of the intermediate compounds V′ or V′a,respectively, i.e. compounds of the formula V or V′, respectively,wherein the sulphonamide hydrogen (R⁴═H) is replaced by C₁-C₄ alkyl,C₃-C₄ cycloalkyl, or C₃-C₄ cycloalkyl-CH₂— (compounds V or V′,respectively, with R⁴═C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or C₃-C₄cycloalkyl-CH₂—), where R⁴ is e.g. a methyl group, the correspondingtrifluoroacetyl group has to be removed by reaction under basicconditions, followed by reprotection with tert.butyl-dicarbonate,reaction of this Boc-protected intermediate V with sodium hydride and analkylating agent, e.g. in case that R⁴ is methyl, methyl iodide. TheN-methylated derivative can then be deprotected at the piperazine orhomopiperazine moiety under standard acidic conditions to yield finalproducts.

Preparation Example 2N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-[1,4]diazepan-1-yl]-benzenesulfonamide

The compound can be prepared as described for PREPARATION EXAMPLE 1starting from commercially available 1-o-tolyl-[1,4]diazepane.

1.2 Preparation of Intermediate Compounds IX Preparation Example 31-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-4-(toluene-4-sulfonyl)-piperazine

3.1 1-(5-Iodo-2-methyl-phenyl)-4-(toluene-4-sulfonyl)-piperazine

9.97 g of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (30.3 mmol)and 5.03 g of potassium iodide (30.3 mmol) in 75 mL of cyclohexanol werestirred for 1 h at 80° C. After addition of 7.7 g of sodium carbonate(72.7 mmol) and 5.65 g of 5-iodo-2-methyl-aniline (24.2 mmol), stirringcontinued for 8 h at 160° C. At room temperature, the mixture wasfiltered, washed with dichloromethane, and the filtrate evaporated todryness. The residue was dissolved in dichloromethane, filtered, and thesolvent evaporated. The remaining residue was trituated with n-heptaneand the crystalline product filtered off, washed several times withn-heptane and dried in vacuo to yield 10.7 g of product.

3.21-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-4-(toluene-4-sulfonyl)-piperazine

0.521 g of 1-(5-Iodo-2-methyl-phenyl)-4-(toluene-4-sulfonyl)-piperazine(1.14 mmol), 0.315 g of sodium 3-(difluoromethoxy)benzenesulfinate (1.37mmol), 0.558 g of cesium carbonate (1.713 mmol), 0.026 g of Pd(dba)₃(0.029 mmol), 0.033 g of Xantphos (0.059 mmol) and 0.381 g oftetrabutylammonium chloride (1.37 mmol) were stirred for 8 h in 10 mL oftoluene. The reaction mixture was filtered and the solvent evaporated.The crude product was purified via silica gel chromatography withtoluene/methanol 20:1 (2.5% triethylamine), fractions containing theproduct combined and the solvents evaporated to yield 0.386 g ofproduct.

II. Preparation of the compounds I Example 1N-(3-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

0.63 g ofN-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonamide(1.28 mmol) were dissolved in 90 ml of methanol, 2.77 ml of 6N aqueoussodium hydroxide (16.6 mmol) added and the reaction stirred at 67° C.for 10 min. 150 mL of water were added, the aqueous layer extracted withethyl acetate, and the organic phase washed with saturated aqueoussodium chloride, dried over sodium sulfate, filtered and the solventevaporated. The residue was converted to the hydrochloride salt byaddition of HCl in diethyl ether. Evaporation to dryness followed bydissolution of the remaining white solid in water and lyophilisation ofthe aqueous phase yielded 0.535 g of product.

ESI-MS: 398.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.45 (s, 1H), 9.0 (broad, 2H),7.3-7.45 (m, 3H), 7.25 (m, 1H), 7.15 (t, 1H), 6.95 (d, 1H), 6.9 (s, 1H),6.85 (d, 1H), 3.25 (broad, 4H), 3.0 (broad, 4H), 2.25 (s, 3H).

Example 23-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamidehydrochloride

The product was obtained as described for Example 1 by reaction ofN-(3-difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-[1,4]diazepan-1-yl]-benzenesulfonamidewith aqueous sodium hydroxide.

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (s, 1H), 9.55 (s, broad, 2H),7.45 (s, 1H), 7.0-7.4 (several m, 4H), 7.0 (d, 1H), 6.95 (s, 1H), 6.8(d, 1H), 4.0 (s, broad, 2H), 3.2 (broad, 6H), 3.0 (m, 2H), 2.25 (s, 3H).

Example 31-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-piperazinehydrochloride

0.75 g of 4-hydroxy-benzoic acid (7.06 mmol) and 2.485 mL of 32% HBr inacetic acid (72.4 mmol) were mixed under stirring and the suspensioncooled to 0° C. 0.379 g of1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-4-(toluene-4-sulfonyl)-piperazine(0.706 mmol) dissolved in 5 mL of acetic acid were added and thereaction mixture stirred for 16 h. Additional 30 equivalents of HBr inacetic acid were added, stirred for 18 h, and the reaction added slowlyto ice water. The pH was adjusted to neutral conditions with addition ofaqueous ammonia, the aqueous layer extracted three times withdichloromethane, the combined organic layers dried over magnesiumsulphate, filtered and the solvent evaporated. The crude product waspurified via silica gel chromatography using toluene/methanol 5:1 (2.5%triethylamine), the solvents evaporated and the residue redissolved in asmall amount of ethyl acetate. The hydrochloride was precipitated byaddition of 2 N hydrochlorid acid in diethyl ether yielding 0.059 g ofproduct.

ESI-MS: 383.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s broad, 2H), 7.8 (d, 1H), 7.7(s, 1H), 7.65 (m, 1H), 7.6 (d, 1H), 7.5 (m, 2H), 7.45 (d, 1H), 7.4 (t,1H), 3.2 (broad, 4H), 3.1 (broad, 4H), 2.3 (s, 3H).

The compounds of Examples 4 to 49 can be prepared in a manner analogousto the preparations described above.

Example 4N-(2-Difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 6.9-7.5 (several m, 9H), 3.5 (broad,8H), 3.1 (s, 3H), 2.75 (s, 3H).

Example 5N-(2-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.4 (broad, 1H), 9.9 (s, 1H), 7.4 (s,1H), 7.05-7.35 (several m, 6H), 6.95 (t, 1H), 3.45 (broad, 2H), 3.2(broad, 2H), 3.1 (broad, 4H), 2.8 (s, 3H), 2.3 (s, 3H).

Example 6N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzene-sulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (broad, 3H), 7.45 (s, 1H), 7.38(d, 1H), 7.32 (d, 1H), 7.15 (d, 1H), 7.05 (t, 1H), 6.95 (s, 1H), 6.9 (d,1H), 3.2 (broad, 4H), 3.0 (broad, 4H), 2.25 (s, 3H), 2.05 (s, 3H).

Example 7N-(4-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 398.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.35 (broad, 1H), 9.55 (broad, 2H),7.25-7.45 (several m, 3H), 7.15 (t, 1H), 7.15 (d, 2H), 7.05 (d, 2H), 3.2(broad, 4H), 3.05 (broad, 4H), 2.25 (s, 3H).

Example 8N-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (broad, 1H), 7.25-7.45 (several m,3H), 7.2 (d, 1H), 7.1 (m, 1H), 6.9 (d, 1H), 3.2 (broad, 4H), 3.05(broad, 4H), 2.3 (broad, 3H).

Example 9N-Cyclopropylmethyl-N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 452.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (broad, 2H), 7.05-7.5 (several m,7H), 7.1 (t, 1H), 3.35 (m, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3(broad, 3H), 0.75 (m, 1H), 0.3 (m, 2H), −0.05 (m, 2H).

Example 10N-Cyclopropylmethyl-N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 452.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (broad, 2H), 6.8-7.55 (several m,8H), 3.4 (m broad, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.35 (broad,3H), 0.75 (m broad, 1H), 0.35 (m broad, 2H), 0.0 (m broad, 2H).

Example 11N-(2-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzene-sulfonamidehydrochloride

ESI-MS: 440.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (broad, 2H), 7.4 (m, 2H), 7.3 (d,1H), 7.25 (d, 2H), 7.1 (t, 1H), 7.1 (m, 2H), 3.4 (m, 2H), 3.2 (broad,4H), 3.05 (broad, 4H), 2.3 (s, 3H), 1.3 (m, 2H), 0.8 (t, 3H).

Example 12N-(3-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzenesulfonamidehydrochloride

ESI-MS: 440.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.4 (broad, 2H), 7.4 (m, 2H), 7.3 (t,1H), 7.25 (d, 1H), 7.15 (d, 1H), 6.95 (s, 1H), 6.95 (d, 1H), 6.85 (s,1H), 3.45 (t, 2H), 3.2 (broad, 4H), 3.0 (broad, 4H), 2.35 (s, 3H), 1.3(m, 2H), 0.8 (t, 3H).

Example 13N-(3-Difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 426.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.35 (broad, 2H), 7.4 (m, 2H), 7.25(t, 1H), 7.25 (d, 1H), 7.2 (d, 1H), 7.0 (s, 1H), 6.95 (d, 1H), 6.85 (s,1H), 3.55 (m, 2H), 3.2 (broad, 4H), 3.0 (broad, 4H), 2.35 (s, 3H), 0.95(t, 3H).

Example 14N-(3-Difluoromethoxy-phenyl)-4,N-dimethyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (broad, 2H), 7.4 (m, 2H), 7.3 (t,1H), 7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.95 (s, 1H), 6.9 (s, 1H),3.55 (m, 2H), 3.2 (broad, 4H), 3.1 (s, 3H), 2.95 (broad, 4H), 2.35 (s,3H).

Example 15N-(2-Difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 426.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (broad, 2H), 7.4 (m, 2H), 7.35(d, 1H), 7.25 (m, 2H), 7.15 (t, 1H), 7.15 (d, 1H), 7.1 (d, 1H), 3.5 (m,2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.35 (s, 3H), 0.95 (t, 3H).

Example 16N-(2-Difluoromethoxy-phenyl)-N-methyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide hydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (broad, 2H), 7.4 (m, 2H), 7.3 (d,1H), 7.2 (m, 2H), 7.1 (t, 1H), 7.1 (m, 2H), 3.2 (broad, 4H), 3.05(broad, 4H), 3.05 (s, 3H), 2.3 (s, 3H).

Example 17N-(2-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 398.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.85 (s, 1H), 9.1 (broad, 2H), 7.3-7.4(m, 3H), 7.25 (d, 1H), 7.1-7.2 (m, 3H), 6.9 (t, 1H), 3.25 (broad, 4H),3.0 (broad, 4H), 2.3 (s, 3H).

Example 18N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzene-sulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.3 (d, 1H), 7.2 (s, 1H), 7.1 (d, 1H),7.0 (d, 1H), 6.8-7.2 (t, 1H), 6.9 (s, 1H), 6.8 (d, 1H), 3.8 (s, 3H), 2.8(s, 8H, 2.1 (s, 3H).

Example 19N-(4-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 414.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.25 (s, 1H), 9.5 (broad, 2H), 7.35(d, 1H), 7.25 (d, 1H), 7.15 (d, 2H), 7.15 (t, 1H), 7.05 (m, 3H), 3.8 (s,3H), 3.2 (broad, 8H).

Example 203-[1,4]Diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.8 (s, 1H), 9.4 (s broad, 2H), 7.4(s, 1H), 7.2-7.3 (m, 3H), 7.1-7.2 (m, 3H), 6.9 (t, 1H), 3.25 (m, 6H),3.0 (m, 2H), 2.3 (s, 3H), 2.0 (m, 2H).

Example 213-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamidehydrochloride

ESI-MS: 426.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.3 (s, 1H), 9.4 (s broad, 2H), 7.4(s, 1H), 7.3 (m, 2H), 7.15 (d, 1H), 7.05 (t, 1H), 6.95 (m, 1H), 6.85 (m,1H), 3.2-3.3 (m, 6H), 3.0 (m, 2H), 2.3 (s, 3H), 2.1 (s, 3H), 2.05 (m,2H).

Example 22N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (broad, 3H), 7.4 (s, 1H), 7.3 (m,2H), 7.1 (d, 1H), 6.9-7.0 (m, 2H), 6.9 (t, 1H), 3.2 (broad, 4H), 3.05(broad, 4H), 2.3 (s, 3H), 2.25 (s, 3H).

Example 23N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.4-9.9 (broad, 3H), 7.4 (s, 1H), 7.3(m, 2H), 7.1 (s, 1H), 6.9-7.0 (m, 2H), 6.85 (t, 1H), 3.2 (broad, 4H),3.05 (broad, 4H), 2.3 (s, 3H), 2.2 (s, 3H).

Example 24N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 414.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (s, 1H), 9.6 (s broad, 2H), 7.4(d, 1H), 7.3 (s, 1H), 7.25 (m, 1H), 7.15 (t, 1H), 7.1 (d, 1H), 7.0 (m,1H), 6.95 (s, 1H), 6.8 (d, 1H), 3.8 (s, 3H), 3.1-3.2 (broad, 8H).

Example 25N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 444.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.05 (s, 1H), 9.3 (s broad, 2H), 7.35(d, 1H), 7.25 (s, 1H), 6.8-7.1 (several m, 5H), 3.8 (s, 1H), 3.7 (s,3H), 3.2 (s broad, 4H), 3.15 (s broad, 4H).

Example 26N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 414.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.8 (s, 1H), 9.7 (s broad, 2H), 7.35(d, 1H), 7.3 (s, 1H), 7.25 (d, 1H), 7.1-7.2 (several m, 3H), 7.05 (d,1H), 7.0 (t, 1H), 3.8 (s, 3H), 3.2 (broad, 8H).

Example 27N-(2-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

27.1 tea-butyl4-(5-(N-(2-(difluoromethoxy)phenyl)sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate

1 g ofN-(2-(difluoromethoxy)phenyl)-4-methoxy-3-(piperazin-1-yl)benzenesulfonamide(2.419 mmol) were dissolved in 15 mL of tetrahydrofuran. 0.674 mL oftriethylamine (4.84 mmol) were added, followed by addition of 0.528 g ofdi-tert-butyl dicarbonate (2.419 mmol) in 2 mL of tetrahydrofurane. Thereaction mixture was stirred at room temperature for 16 h. Afterevaporation of the solvent, the residue was dissolved indichloromethane, washed with 5% aqueous citric acid. The organic phasewas washed with saturated aqueous sodium chloride, dried over sodiumsulphate, filtered, and the solvent evaporated. The crude productcontaining ca. 25% of the bis-boc derivative was used without furtherpurification in the next step (1.2 g).

27.2 tert-butyl4-(5-(N-(2-(difluoromethoxy)phenyl)methyl-sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate

0.15 g of tert-butyl4-(5-(N-(2-(difluoromethoxy)phenyl)sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate(0.219 mmol) were dissolved in 5 mL of dimethylformamide. 11.4 mg ofsodium hydride (0.285 mmol, 60%) were added and the reaction stirred at50° C. for 20 min. At room temperature, 0.018 mL of methyl iodide (0.285mmol) were added. Stirring was continued for 16 h at room temperaturefollowed by addition of additional 0.018 mL of methyl iodide andstirring for 16 h. The solvent was evaporated, the residue dissolved indichloromethane and washed with saturated aqueous sodium chloride. Theorganic layer was dried over sodium sulfate, filtered and the solventevaporated. Purification via silica gel chromatography (RedisepNP-cartridge) with cyclohexane/ethyl acetate (0-50%) yielded 0.104 g ofthe title compound.

ESI-MS: 528.2 [M+H]⁺

27.3N-(2-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

0.104 g tert-butyl4-(5-(N-(2-(difluoromethoxy)phenyl)methyl-sulfamoyl)-2-methoxyphenyl)piperazine-1-carboxylate(0.197 mmol) were dissolved in 5 mL of dichloromethane. At roomtemperature, 0.296 mL of 2 N aqueous hydrochloric acid (0.591 mmol) wereadded and the reaction stirred for 16 h and 2 h at 35° C. After additionof methanol, stirring continued for 1 h before the solvents wereevaporated and the residue co-destilled several times with diethyl etherto remove residual hydrochloric acid. The remaining solid was dissolvedin water (pH 4), extracted several times with dichloromethane, andaqueous layer lyophilized to yield 0.08 g of the title compound.

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.3 (s broad 2H), 7.45 (m, 1H), 7.4(m, 1H), 7.25 (m, 2H), 7.2 (d, 1H), 7.1 (d, 1H), 7.1 (t, 1H), 7.0 (s,1H), 3.9 (s, 3H), 3.2 (s broad, 4H), 3.15 (s broad, 4H), 3.05 (s, 3H).

Examples 9, 10, 11, 12, 13, 14, 15, 16, 28, 29, 30, 31, 32, 33, 34, 36,39, and 43 were prepared as described for Example 27, using eithermethyl iodide, ethyl iodide, propyl bromide, isopropyl bromide orcyclopropyl-methylen-bromide as alkylating reagents.

Example 28N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 458.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (s broad, 2H), 9.05 (s broad, 1H),7.2 (m, 1H), 7.25 (m, 2H), 7.05 (t, 1H), 6.95 (m, 1H), 6.9 (s, 1H), 6.8(s, 1H), 3.9 (s, 3H), 3.85 (s, 3H), 3.2 (broad, 8H), 3.05 (s, 3H).

Example 29N-(3-Difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 442.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s broad, 2H), 7.4 (m, 1H), 7.25(t, 1H), 7.25 (m, 1H), 7.1-7.2 (several m, 2H), 6.9 (d, 1H), 6.8 (s,2H), 3.85 (s, 3H), 3.5 (m, 2H), 3.2 (s broad, 4H), 3.15 (s broad, 4H),0.9 (t, 3H).

Example 30N-(3-Difluoromethoxy-4-methoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 472.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.3 (s broad, 2H), 7.25 (d, 1H),7.1-7.2 (m, 2H), 7.0 (t, 1H), 6.95 (m, 1H), 6.9 (s, 1H), 6.8 (s, 1H),3.9 (s, 3H), 3.85 (s, 3H), 3.5 (m, 2H), 3.2 (s broad, 4H), 3.15 (sbroad, 4H), 0.95 (t, 3H).

Example 31N-(2-Difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s, broad, 2H), 7.45 (m, 1H), 7.35(m, 1H), 7.2-7.3 (m, 2H), 7.2 (m, 1H), 7.15 (t, 1H), 7.1 (d, 1H), 7.0(s, 1H), 3.9 (s, 3H), 3.5 (m, 2H), 3.1-3.25 (s broad, 8H), 0.95 (t, 3H).

Example 32N-(3-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (s broad, 2H), 9.0 (s, broad, 1H),7.4 (m, 1H), 7.3 (t, 1H), 7.25 (m, 1H), 7.1-7.2 (m, 2H), 7.0 (d, 1H),6.95 (s, 1H), 6.7 (s, 1H), 3.9 (s, 3H), 3.2 (s broad, 4H), 3.1 (s broad,4H), 2.5 (m, 3H).

Example 33N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamidehydrochloride

ESI-MS: 486.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.3 (s broad, 2H), 7.25 (d, 1H), 7.15(m, 2H), 7.0 (t, 1H), 6.95 (d, 1H), 6.85 (d, 1H), 6.75 (s, 1H), 3.9 (s,3H), 3.8 (s, 3H), 3.4 (t, 2H), 3.2 (broad, 4H), 3.1 (broad, 4H), 1.8 (m,2H), 0.8 (t, 3H).

Example 34N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamidehydrochloride

ESI-MS: 456.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (s broad, 2H), 7.4 (m, 1H), 7.25(d, 2H), 7.15 (m, 2H), 6.95 (d, 1H), 6.85 (s, 1H), 6.8 (s, 1H), 3.85 (s,3H), 3.45 (t, 2H), 3.2 (broad, 4H), 3.1 (broad, 4H), 1.8 (m, 2H), 0.8(t, 3H).

Example 35N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 7.45 (d, 1H), 7.2 (m, 2H), 6.8-7.0(several m, 4H), 6.45 (t, 1H), 3.9 (s, 3H), 3.0 (s, 4H), 2.6 (s, 4H),2.35 (s, 3H).

Example 36N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamidehydrochloride

ESI-MS: 456.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.0 (broad, 2H), 7.45 (m, 1H), 7.35(m, 1H), 6.9-7.3 (several m, 6H), 3.9 (s, 3H), 3.4 (t, 2H), 3.2 (broad,4H), 3.15 (broad, 4H), 1.3 (m, 2H), 0.8 (t, 3H).

Example 37N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (s broad, 1H), 9.7 (s, 1H), 7.4(d, 1H), 7.3 (m, 2H), 7.05-7.2 (several m, 4H), 6.95 (t, 1H), 3.85 (s,3H), 3.45 (m, 4H), 3.2 (m, 2H), 2.95 (m, 2H), 2.8 (d, 3H).

Example 38N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 458.1 [M+H]⁺

¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 7.35 (m, 2H), 7.0 (m, 1H), 6.9 (s, 1H),6.8 (m, 2H), 6.5 (t, 1H), 3.9 (s, 3H), 3.8 (s, 3H), 3.2 (broad, 4H), 2.8(broad, 4H), 2.5 (s, broad, 3H).

Example 39N-(2-Difluoromethoxy-phenyl)-N-isopropyl-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 440.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (s broad, 2H), 6.95-7.55 (severalm, 8H), 4.3 (m, 1H), 3.2 (broad, 4H), 3.1 (broad, 4H), 2.3 (s, 3H), 1.0(d, 3H), 0.9 (d, 3H).

Example 40N-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.4 (s, 1H), 9.6 (s broad, 2H), 7.35(d, 1H), 7.25 (s, 1H), 7.2 (d, 1H), 7.1 (m, 2H), 6.9 (d, 1H), 3.85 (s,3H), 3.2 (broad, 8H).

Example 41N-(2-Difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 384.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.9 (s, 1H), 9.75 (s broad, 2H), 7.4(m, 2H), 7.25 (m, 2H), 7.1-7.2 (m, 4H), 6.95 (t, 1H), 3.4 (broad, 4H),3.15 (broad, 4H),

Example 42N-(2-Difluoromethoxy-phenyl)-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 398.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.45 (s broad, 1H), 9.9 (s broad,1H), 7.35-7.45 (m, 2H), 7.25 (m, 2H), 7.1-7.2 (m, 4H), 7.0 (t, 1H),3.0-3.9 (broad, 8H), 2.75 (s, 3H).

Example 43N-(2-Difluoromethoxy-phenyl)-N-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 398.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s broad, 2H), 7.5 (m, 1H), 7.45(m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 7.1 (m, 3H), 7.05 (t, 1H), 3.4(broad, 4H), 3.2 (broad, 4H), 3.1 (s, 3H).

Example 44N-(2-Difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.5 (broad, 1H), 7.55 (m, 1H), 7.5(m, 1H), 7.45 (d, 1H), 7.25 (m, 2H), 7.05-7.2 (several m, 4H), 3.4(broad, 8H), 3.1 (s, 3H), 2.8 (s, 3H).

Example 45 1-[3-(3-Difluoromethoxy-benzenesulfonyl)-phenyl]-piperazinehydrochloride

ESI-MS: 369.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (s broad, 2H), 7.85 (d, 1H), 7.75(s, 1H), 7.7 (m, 1H), 7.45-7.55 (several m, 3H), 7.4 (t, 1H), 7.4 (d,1H), 7.3 (m, 1H), 3.5 (s broad, 4H), 3.15 (s broad, 4H).

Example 461-[3-(3-Difluoromethoxy-benzenesulfonyl)-phenyl]-4-methyl-piperazinehydrochloride

ESI-MS: 383.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.85 (d, 1H), 7.8 (s, 1H), 7.7 (m,1H), 7.45-7.55 (several m, 3H), 7.4 (d, 1H), 7.4 (t, 1H), 7.3 (d, 1H),3.95 (d, 2H), 3.65 (d, 2H), 3.25 (m, 2H), 3.15 (m, 2H), 2.8 (d, 3H).

Example 471-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazinehydrochloride

ESI-MS: 399.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (s broad, 2H), 7.8 (d, 1H), 7.7(s, 1H), 7.65 (m, 2H), 7.45 (d, 1H), 7.4 (t, 1H), 7.4 (m, 1H), 7.2 (d,1H), 3.85 (s, 3H), 3.25 (s broad, 4H), 3.2 (s broad, 4H).

Example 481-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-4-methyl-piperazinehydrochloride

ESI-MS: 413.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.8 (d, 1H), 7.75 (s, 1H), 7.65 (m,2H), 7.5 (d, 1H), 7.4 (t, 1H), 7.4 (s, 1H), 7.2 (d, 1H), 3.85 (s, 3H),3.55 (m, 2H), 3.45 (m, 2H), 3.05-3.2 (m, 4H), 2.8 (s, 3H).

Example 491-[5-(3-Difluoromethoxy-4-methoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazinehydrochloride

ESI-MS: 429.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.55 (s broad, 2H), 7.85 (d, 1H), 7.7(s, 1H), 7.6 (d, 1H), 7.3 (m, 2H), 7.2 (t, 1H), 7.17 (d, 1H), 3.9 (s,3H), 3.85 (s, 3H), 3.25 (s broad, 4H), 3.2 (s broad, 4H).

Example 50N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (broad, 1H), 9.0 (broad, 2H), 7.35(d, 1H), 7.27 (s, 1H), 7.1 (s, 1H), 7.05 (d, 1H), 6.95 (m, 2H), 6.85 (t,1H), 4.1 (q, 2H), 3.2 (broad, 4H), 3.15 (broad, 4H), 2.2 (s, 3H), 1.35(t, 3H).

Example 51N-(3,4-Bis-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 494 [M+H]⁺

Example 52N-(3,4-Bis-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 464.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.6 (broad, 1H), 9.6 (broad, 2H),7.3-7.45 (m, 3H), 6.9-7.3 (several m, 5H), 3.2 (broad, 4H), 3.05 (broad,2H), 2.3.

Example 53N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 462 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): 8]ppm] 10.5 (broad, 1H), 10.05 (broad, 1H),7.4 (d, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 7.23 (d, 1H), 7.18 (d, 1H), 7.1(d, 1H), 7.0 (t, 1H), 3.85 (s, 3H), 3.5 (broad, 4H), 3.2 (broad, 2H),3.0 (broad, 2H), 2.8 (s, 3H).

Example 54N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide

ESI-MS: 440.1 [M+H]⁺

Example 55N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.6 (broad, 1H), 9.6 (broad, 1H),7.35 (d, 1H), 7.05-7.25 (several m, 4H), 6.9 (d, 1H), 6.8 (s, 1H), 3.85(s, 3H), 3.1-3.7 (broad, 8H), 3.4 (s, 3H), 2.0 (s, 3H).

Example 56N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 446.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.4 (very broad, 2H), 7.48 (s, 1H),7.4 (m, 2H), 7.33 (s, 1H), 7.23 (d, 1H), 7.18 (d, 1H), 6.98 (t, 1H),2.95-3.7 (broad, 8H), 2.9 (s, 3H), 2.3 (s, 3H).

Example 57N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 448.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.05 (s, 1H), 9.1 (broad, 2H), 7.4(d, 1H), 7.32 (m, 2H), 7.22 (d, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 7.0 (t,1H), 3.85 (s, 3H), 3.2 (broad, 4H), 3.15 (broad, 4H).

Example 58N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.2-7.4 (several m, 3H), 7.15 (d, 1H),7.1 (t, 1H), 6.88 (d, 1H), 6.82 (s, 1H), 3.1 (broad, 4H), 2.9 (broad,4H), 2.3 (s, 3H), 1.95 (s, 3H).

Example 59N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.65-9.8 (broad, 3H), 7.3 (d, 1H), 7.2(s, 1H), 7.18 (d, 1H), 7.12 (t, 1H), 7.1 (d, 1H), 6.9 (d, 1H), 6.75 (s,1H), 3.8 (s, 3H), 3.15 (broad, 8H), 1.95 (s, 3H).

Example 60N-(3,4-Bis-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 480.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.55 (s, 1H), 9.5 (s, 2H), 7.43 (d,1H), 7.25 (m, 2H), 6.9-7.15 (m, 5H), 3.9 (s, 3H), 3.2 (broad, 8H).

Example 61N-(5-Chloro-2-difluoromethoxy-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 446 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.25 (broad, 1H), 9.55 (broad, 2H),7.5 (s, 1H), 7.4 (m, 2H), 7.3 (s, 1H), 7.25 (d, 1H), 7.2 (d, 1H), 7.0(t, 1H), 3.25 (broad, 4H), 3.05 (broad, 4H), 2.7 (q, 2H), 1.2 (t, 3H).

Example 62N-(2-Difluoromethoxy-4-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 426.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5 (broad, 2H), 7.3-7.4 (m, 3H), 7.1(d, 1H), 6.97 (d, 1H), 6.93 (s, 1H), 6.9 (t, 1H), 3.2 (broad, 4H), 3.0(broad, 4H), 2.68 (q, 2H), 2.25 (s, 3H), 1.18 (t, 3H).

Example 63N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((R)-3-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 426.2 [M+H]⁺

¹H NMR (methanol-d₄, 400 Hz): δ [ppm] 7.3-7.45 (m, 4H), 6.9-7.05 (m,2H), 6.4 (t, 1H), 2.7-3.7 (several m, 7H), 2.4 (s, 3H), 2.3 (s, 3H), 1.4(d, 3H).

Example 64N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((S)-3-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 426.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.85 (s, 1H), 9.65 (broad, 1H), 9.4(broad, 1H), 7.4 (s, 1H), 7.35 (s, 2H), 7.1 (s, 1H), 6.95-7.0 (m, 2H),7.0 (t, 1H), 3.4 (broad, 3H), 3.1 (m, 2H), 2.95 (m, 1H), 2.8 (m, 1H),2.3 (s, 3H), 2.22 (s, 3H), 1.3 (d, 3H).

Example 65N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 426.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.85 (broad, 1H), 9.6 (broad, 2H),7.45 (s, 1H), 7.4 (m, 2H), 7.1 (s, 1H), 6.95-7.0 (m, 2H), 6.85 (t, 1H),3.22 (broad, 4H), 3.02 (broad, 4H), 2.68 (q, 2H), 2.2 (s, 3H), 1.15 (t,3H).

Example 66N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.1 (broad, 1H), 7.33 (d, 1H), 7.28(d, 1H), 7.08-7.15 (m, 2H), 7.05 (d, 1H), 6.8 (d, 1H), 3.8 (s, 3H), 2.9(broad, 4H), 2.45 (broad, 4H), 2.2 (s, 3H).

Example 67N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

0.429 gN-(2-(difluoromethoxy)-5-methylphenyl)-4-methoxy-3-(piperazin-1-yl)benzenesulfonamide(1.004 mmol) were dissolved in 5 mL of dichloromethane. 0.086 mL ofacetic acid (1.505 mmol) and 0.319 g of sodium triacetoxyborohydride(3.01 mmol) were added. After stirring for 10 min, 0.083 mL of aqueousformaldehyde solution (3.01 mmol) were added and the reaction stirredfor 72 h at room temperature. The solvents were evaporated and theresidue purified via preparative silica gel chromatography (Super Flashcartridge (Interchim)) using a dichloromethane (+0.1% triethylamine) andmethanol gradient as eluent. Fractions containing the product werecombined, the solvents evaporated, and the product converted to thehydrochloride salt by addition of hydrochloric acid in diethyl ether andsubsequent evaporation to dryness (yield 0.169 g of product).

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (broad, 1H), 7.3 (d, 1H), 7.2 (s,1H), 7.1 (s, 1H), 6.9-7.05 (several m, 3H), 6.8 (t, 1H), 3.8 (s, 3H),2.9 (broad, 4H), 2.45 (broad, 4H), 2.2 (two s, 6H).

Example 68N-(3-Difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 384.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.6 (s, 1H), 9.85 (broad, 1H), 9.45(broad, 2H), 7.4 (m, 2H), 7.2-7.35 (m, 3H), 7.2 (t, 1H), 7.0 (m, 1H),6.95 (s, 1H), 6.85 (d, 1H), 3.15-3.65 (broad, 8H).

Example 69N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 446.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.85 (broad, 1H), 9.75 (s, 1H),7.2-7.35 (m, 3H), 7.0-7.1 (m, 3H), 7.07 (t, 1H), 3.85 (s, 3H), 3.5 (m,4H), 3.18 (m, 2H), 3.02 (m, 2H), 2.85 (s, 3H).

Example 70N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.2 (broad, 1H), 9.6 (s, 1H), 7.3 (m,2H), 7.12 (d, 1H), 7.05 (d, 1H), 6.9-7.0 (several m, 2H), 6.92 (t, 1H),3.8 (s, 3H), 3.45 (m, 4H), 3.17 (m, 2H), 3.05 (m, 2H), 2.8 (s, 3H), 2.25(s, 3H).

Example 71N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 432.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.3 (s, 1H), 9.75 (broad, 2H),7.15-7.5 (several m, 6H), 7.05 (t, 1H), 3.2 (broad, 4H), 3.07 (broad,4H), 2.3 (s, 3H).

Example 72N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 463.9306 1H-NMR (DMSO-d6, 400 Hz): d[ppm] 9.7 (broad, 1H), 9.6 (broad, 2H), 7.35 (d, 1H), 7.3 (s, 1H), 7.1(s, 1H), 7.05 (d, 1H), 6.9-7.0 (m, 2H), 6.85 (t, 1H), 3.8 (s, 3H),3.1-3.25 (broad, 8H) 2.2 (s, 3H).

Example 73N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.3 (d, 1H), 7.2 (s, 1H), 7.15 (d,1H), 6.95 (d, 1H), 6.9 (d, 1H), 6.85 (t, 1H), 3.8 (s, 3H), 2.8-2.95(broad, 8H) 2.2 (s, 3H).

Example 74N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 416.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.15-7.35 (several m, 4H), 7.1 (t,1H), 6.8-6.95 (m, 2H), 3.0 (broad, 4H), 2.85 (broad, 4H), 2.2 (s, 3H).

Example 75N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 426.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.35 (broad, 1H), 10.4 (s, 1H), 7.4(s, 1H), 7.35 (m, 2H), 7.15 (d, 1H), 7.1 (t, 1H), 7.0 (s, 1H), 6.9 (m,1H), 3.5 (broad, 2H), 3.2 (broad, 2H), 3.1 (broad, 4H), 2.8 (s, 3H), 2.3(s, 3H), 2.1 (s, 3H).

Example 76N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.4 (broad, 1H), 7.4 (m, 1H), 7.37 (m,2H), 7.03 (d, 1H), 6.9 (t, 1H), 6.87 (s, 1H), 6.65 (d, 1H), 3.7 (s, 3H),3.25 (broad, 4H), 3.0 (broad, 4H), 2.25 (s, 3H).

Example 77N-(5-Difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidetrifluoroacetate

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.6 (s, 1H), 7.3-7.45 (m, 3H), 7.07(d, 1H), 7.05 (t, 1H), 6.95 (m, 2H), 3.55 (s, 3H), 3.55 (broad, 2H), 3.2(broad, 4H), 2.9 (broad, 2H), 2.9 (s, 3H), 2.3 (s, 3H).

Example 78

N-(2-Difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidetrifluoroacetate

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 7.5 (d, 1H), 7.37 (s, 1H), 7.2 (d, 1H),6.93 (m, 2H), 6.6 (d, 1H), 6.2 (t, 1H), 3.8 (s, 3H), 3.67 (m, 2H), 3.2(m, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 2.9 (s, 3H), 2.3 (s, 3H).

Example 79N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidetrifluoroacetate

ESI-MS: 430.1 [M+H]⁺

¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 7.63 (m, 1H), 7.38 (m, 2H), 6.95 (m,1H), 6.85 (s, 1H), 6.78 (d, 1H), 6.27 (t, 1H), 3.7 (m, 2H), 3.25 (m,2H), 2.95-3.2 (broad, 4H), 2.9 (s, 3H), 2.3 (s, 3H).

Example 80

N-(5-Difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidetrifluoroacetate

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (CDCl₃, 400 Hz): δ [ppm] 9.8 (broad, 2H), 7.52 (d, 1H), 7.38 (s,2H), 7.1 (s, 1H), 6.8 (m, 1H), 6.7 (m, 1H), 6.45 (t, 1H), 3.7 (s, 3H),3.35 (broad, 4H), 3.1 (broad, 4H), 2.3 (s, 3H).

Example 81N-(2-Difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.7 (broad, 2H), 7.45 (s, 1H), 7.35(m, 2H), 7.05 (d, 1H), 6.8 (d, 1H), 6.8 (t, 1H), 6.7 (d, 1H), 3.65 (s,3H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H).

Example 82N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 432.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.15-7.35 (several m, 3H), 6.9-7.05(several m, 3H), 6.85-7.15 (t, 1H), 3.8 (s, 3H), 3.05 (m, 4H), 3.0 (m,4H).

Example 83N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.35 (d, 1H), 7.15-7.2 (m, 2H), 7.05(s, 1H), 7.0 (d, 1H), 6.85 (d, 1H), 3.8 (s, 3H), 2.85-3.0 (broad, 8H).

Example 84N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.4 (s, 1H), 9.25 (broad, 2H), 7.4(s, 1H), 7.35 (m, 2H), 7.28 (d, 1H), 7.15 (m, 1H), 6.88 (d, 1H), 3.25(broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H).

Example 85N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 428.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 8.8-10.4 (very broad, 3H), 7.3-7.4 (m,3H), 7.03 (d, 1H), 6.95 (t, 1H), 6.85-7.0 (m, 2H), 3.75 (s, 3H), 3.2(broad, 4H), 3.05 (broad, 4H), 2.25 (s, 3H).

Example 86N-(3-Difluoromethoxy-4-methyoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 443.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.3 (very broad, 1H), 10.15 (s, 1H),7.4 (s, 1H), 7.3 (m, 2H), 7.05 (d, 1H), 6.95 (m, 2H), 6.95 (t, 1H), 3.7(s, 3H), 3.05-3.5 (broad, 8H), 2.8 (s, 3H), 2.25 (s, 3H).

Example 87N-(4-Difluoromethoxy-3-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 427.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.3 (s broad, 1H), 7.3-7.4 (m, 3H),7.15 (d, 1H), 7.0 (t, 1H), 6.95 (s, 1H), 6.88 (m, 1H), 3.4 (broad, 4H),3.1 (broad, 4H), 2.8 (s, 3H), 2.25 (s, 3H), 2.1 (s, 3H).

Example 88N-(4-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 413.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.25 (s broad, 1H), 7.3-7.4 (m, 3H),7.1 (dd, 2H), 7.05 (dd, 2H), 7.05 (t, 1H), 3.4 (broad, 4H), 3.1 (broad,4H), 2.75 (s, 3H), 2.3 (s, 3H).

Example 89N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 442.2 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.2 (s broad, 1H), 7.4 (d, 1H), 7.3(s, 2H), 7.15 (d, 1H), 7.08 (m, 1H), 7.03 (t, 1H), 6.95 (s, 1H), 6.9 (d,1H), 3.8 (s, 3H), 3.0-3.6 (broad, 8H), 2.8 (s, 3H), 2.1 (s, 3H).

Example 90N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide

ESI-MS: 458.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.42 (d, 1H), 7.27 (s, 1H), 7.05 (m,2H), 6.9 (d, 1H), 6.9 (t, 1H), 6.7 (d, 1H), 3.8 (s, 3H), 3.7 (s, 3H),3.1 (broad, 4H), 2.9 (broad, 4H), 2.5 (s, 3H).

Example 91N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 427.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.3 (broad, 1H), 9.7 (s broad, 1H),7.4 (s, 1H), 7.25-7.35 (m, 2H), 7.1 (d, 1H), 6.97 (d, 1H), 6.95 (s, 1H),6.9 (t, 1H), 3.0-3.5 (broad, 8H), 2.8 (s, 3H), 2.3 (s, 3H), 2.25 (s,3H).

Example 92N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 427.5 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.3 (broad, 1H), 9.8 (s broad, 1H),7.4 (s, 1H), 7.32 (s, 2H), 7.1 (s, 1H), 7.0 (m, 2H), 6.85 (t, 1H), 6.9(t, 1H), 3.0-3.5 (broad, 8H), 2.8 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H).

Example 93N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamidehydrochloride

ESI-MS: 444.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 8.4 (broad, 1H), 7.42 (m, 1H), 7.24(s, 1H), 7.0-7.15 (m, 2H), 6.85-7.0 (m, 2H), 6.7 (m, 1H), 3.8 (s, 3H),3.7 (s, 3H), 3.0 (broad, 8H).

Example 94N-(3-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.5 (s broad, 1H), 7.2-7.4 (severalm, 3H), 7.15 (t, 1H), 7.0 (d, 1H), 6.92 (s, 1H), 6.82 (d, 1H), 3.0-3.5(broad, 8H), 2.8 (s, 3H), 2.25 (s, 3H).

Example 95N-(4-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 428.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 11.3 (broad, 1H), 10.2 (s, 1H), 7.38(d, 1H), 7.3 (s, 1H), 7.15 (dd, 2H), 7.07 (m, 3H), 7.1 (t, 1H), 3.8 (s,3H), 3.4 (broad, 4H), 3.1 (broad, 4H), 2.8 (s, 3H).

Example 963-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.53 (s, 1H), 9.55 (s, 2H), 7.45 (s,1H), 7.2-7.4 (m, 3H), 7.15 (t, 1H), 7.0 (d, 1H), 6.95 (s, 1H), 6.8 (d,1H), 3.25 (broad, 6H), 3.05 (m, 2H), 2.25 (s, 3H), 2.05 (broad, 2H).

Example 973-[1,4]Diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamidehydrochloride

ESI-MS: 412.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.8 (s, 1H), 9.4 (s, 2H), 7.4 (s, 1H),7.2-7.35 (m, 3H), 7.1-7.2 (m, 3H), 6.9 (t, 1H), 3.25 (broad, 6H), 3.05(m, 2H), 2.3 (s, 3H), 2.05 (broad, 2H).

Example 983-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamidehydrochloride

ESI-MS: 426.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 10.3 (s, 1H), 9.45 (s, 2H), 7.4 (s,1H), 7.3 (s, 2H), 7.15 (d, 1H), 7.05 (t, 1H), 6.95 (s, 1H), 6.87 (d,1H), 3.25 (broad, 6H), 3.05 (m, 2H), 2.3 (s, 3H), 2.1 (s, 3H), 2.05(broad, 2H).

Example 99N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 440.2 [M+H]⁺

Example 100N-(2-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 426.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 9.5-11.0 (very broad, 2H), 7.4 (s,1H), 7.2-7.35 (m, 3H), 7.1-7.2 (m, 3H), 6.93 (t, 1H), 3.4 (broad, 6H),3.05 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.15 (broad, 2H).

Example 101N-(3-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamidehydrochloride

ESI-MS: 426.2 [M+H]⁺

Example 102N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-ylbenzenesulfonamide

Example 103N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-N-methyl-3-piperazin-1-ylbenzenesulfonamide

Example 104N-(5-Difluoromethoxy-2-methylphenyl)-4-fluoro-3-piperazin-1-ylbenzenesulfonamide

Example 105N-(5-Difluoromethoxy-2-methylphenyl)-4-fluoro-N-methyl-3-piperazin-1-ylbenzenesulfonamide

Example 106N-(2-Difluoromethoxy-4-methylphenyl)-4-ethoxy-3-piperazin-1-ylbenzenesulfonamide

ESI-MS: 442.1 [M+H]⁺

¹H-NMR (DMSO-d₆, 400 Hz): δ [ppm] 7.3 (d, 1H), 7.25 (s, 1H), 7.15 (d,1H), 7.0 (m, 1H), 6.95 (m, 2H), 6.9 (t, 1H), 4.07 (q, 2H), 3.15 (b, 4H),3.11 (b, 4H), 2.2 (s, 3H), 1.35 (t, 3H).

III. Biological Investigations

Displacement of Radioligands Binding to the Following Cloned HumanReceptors

1. Preparation of Membranes by Ultrasonic Treatment and DifferentialCentrifugation

Cells from stable clonal cell lines expressing the correspondingreceptor (5-HT₆, α₁-adrenergic, dopamine D₂ or histamine H₁ receptors)were washed with PBS (w/o Ca⁺⁺, Mg⁺⁺) and harvested in PBS with 0.02%EDTA. The cells were collected by centrifugation at 500 g for 10 min. at4° C., washed with PBS and centrifuged (500 g, 10 min. 4° C.). Thepellets were stored at −80° C. until use. For membrane preparation, thethawed cell pellet was resuspended in ice-cold sucrose buffer (0.25 Msucrose, 10 mM Hepes (pH 7.4), 1 mM Phenylmethylsulfonyl fluoride (PMSF)in DMSO, 5 μg/ml Pepstatin-A, 3 mM EDTA, 0.025% Bacitracin) andhomogenized with a Branson Sonifier W-250 (Settings: Timer 4; OutputControl 3; Duty Cycle constant; 2 to 3 cycles). Cell disruption waschecked with the aid of a microscope. Remaining unbroken cells werepelleted at 1.000 g for 10 min. at 4° C. The sucrose buffer supernatantwas then centrifuged at 60.000 g for 1 h at 4° C. (BeckmanUltrazentrifuge XL 80). The pellet was resuspended in 30 ml ice-coldTris buffer (20 mM TRIS (pH 7.4), 5 μg/ml Pepstatin A, 0.1 mM PMSF, 3 mMEDTA) by pipetting through a 10 ml serological pipet and centrifuged for1 h at 4° C. at 60.000 g. A final resuspension was performed in a smallvolume of ice-cold Tris buffer (see above) by pressing through aserological pipet followed by ultrasonic treatment with a BransonSonifier W-250 (Settings: Timer 1; Output Control 3; Duty Cycleconstant; 1 cycle). Protein concentration was determined (BCA-Kit;Pierce) and aliquots stored at −80° C. or in liquid nitrogen forlong-term storage.

2. Receptor Binding Experiments

All receptor binding experiments were carried out in the correspondingassay buffer in a total volume of 200 μl in the presence of variousconcentrations of test compound (10⁻⁵ M to 10⁻⁹ M, tenfold serialdilution, duplicate determinations). The assays were terminated byfiltration on polyethylenimine (PEI 0.1% or 0.3%) presoaked PackardUnifilter Plates (GF/C or GF/B) with a Tomtec Machin U 96 well-plateharvester. After the plates had been dried for 2 h at 55° C. in a dryingchamber scintillation cocktail (BetaPlate Scint; PerkinElmer) was added.Radioactivity was measured in a Microbeta Trilux two hours after theaddition of the scintillation mixture. Data derived from liquidscintillation counting were analysed by iterative non-linear regressionanalysis with the use of the Statistical Analysis System (SAS): aprogram similar to “LIGAND” as described by Munson and Rodbard(Analytical Biochemistry 107, 220-239 (1980).

a) 5-HT₆ Receptor Binding Assay

HEK293 cells stably expressing the h-5-HT₆ receptor (NCBI ReferenceSequence XM 001435) were cultured in RPMI1640 medium supplemented with25 mM HEPES, 10% fetal calf serum and 1-2 mM glutamine. The membranepreparation was performed as described in section 1. For these membranesa K_(D) of 1.95 nM for [³H]-LSD (Lysergic Acid Diethylamide; Amersham,TRK1038) was determined by means of saturation binding experiments. Onthe day of the assay, the membranes were thawed, diluted in assay buffer(50 mM Tris-HCl, 5 mM CaCl₂, 0.1% ascorbic acid, 10 μM pargyline, pH7.4) to a concentration of 8 μg protein/assay and homogenized by gentlevortexing For inhibition studies, 1 nM [³H]-Lysergic Acid Diethylamidewas incubated in the presence of various concentrations of test compoundin assay buffer. Non-specific binding was defined with 1 μMmethiothepin. The binding reaction was carried out for 3.5 h at roomtemperature. During the incubation, the plates were shaken on a plateshaker at 100 rpm and terminated by filtration on Packard Unifilter GF/C(0.1% PEI) plates, followed by 2 wash cycles with ice-cold 50 mMTris-HCl, 5 mM CaCl₂.

a) Dopamine D₂ Receptor Binding Assay

HEK293 cells stably expressing the dopamine D₂ receptor (NCBI ReferenceSequence NM_(—)000795) were cultured in RPMI1640 medium supplementedwith 25 mM HEPES, 10% fetal calf serum and 1-2 mM glutamine. Themembrane preparation was performed as described in section 1. For thesemembranes a K_(D) of 0.22 nM for [¹²⁵I]-iodospiperone (PerkinElmer LifeSciences, NEX284) was determined by means of saturation bindingexperiments. On the day of the assay, the membranes were thawed, dilutedin assay buffer (50 mM Tris-HCl, 120 mM NaCl, 5 mM MgCl₂, 5 mM KCl, 1.5mM CaCl₂, pH 7.4) to a concentration of 15 μg protein/assay andhomogenized by gentle vortexing. For inhibition studies, 0.01 nM[¹²⁵I]-iodospiperone (PerkinElmer Life Sciences, NEX284) was incubatedin the presence of various concentrations of test compound in assaybuffer. Non-specific binding was defined with 1 μM haloperidol. Thebinding reaction was carried out for 1 h at room temperature andterminated by filtration on Packard Unifilter GF/B (0.1% PEI) plates,followed by 6 wash cycles with an ice-cold 7% polyethylenglycolsolution.

b) α₁-Adrenergic Receptor Binding Assay

CHO-K₁ cells stably expressing the α₁-adrenergic receptor (NCBIReference Sequence NM_(—)033303) were cultured in RPMI1640 mediumsupplemented with 25 mM HEPES, 10% fetal calf serum and 1-2 mMglutamine. The membrane preparation was performed as described insection 1. For these membranes a K_(D) of 0.12 nM for [³H]-prazosine(PerkinElmer Life Sciences, NET823) was determined by means ofsaturation binding experiments. On the day of the assay, the membraneswere thawed, diluted in assay buffer (50 mM Tris-HCl, pH 7.4) to aconcentration of 4 μg protein/assay and homogenized by gentle vortexing.For inhibition studies, 0.1 nM [³H]-prazosine (PerkinElmer LifeSciences, NET823) was incubated in the presence of variousconcentrations of test compound in assay buffer. Non-specific bindingwas defined with 1 μM phentolamine. The binding reaction was carried outfor 1 h at room temperature and terminated by filtration on PackardUnifilter GF/C (0.1% PEI) plates, followed by 3 wash cycles withice-cold assay buffer.

c) H₁ Receptor Binding Assay

CHO-K₁ cells stably expressing the histamine H₁ receptor(Euroscreen-ES-390-C, NCBI Reference Sequence NM_(—)000861) werecultured in RPMI1640 medium supplemented with 25 mM HEPES, 10% fetalcalf serum and 1-2 mM glutamine. The membrane preparation was performedas described in section 1. For these membranes a K_(D) of 0.83 nM for[³H]-pyrilamine (PerkinElmer Life Sciences, NET594) was determined bymeans of saturation binding experiments. On the day of the assay, themembranes were thawed, diluted in assay buffer (50 mM Na₂HPO₄, 50 mMKH₂PO₄, pH 7.4) to a concentration of 6 μg protein/assay and homogenizedby gentle vortexing. For inhibition studies, 1 nM [³H]-pyrilamine(PerkinElmer Life Sciences, NET594) was incubated in the presence ofvarious concentrations of test compound in assay buffer. Non-specificbinding was defined with 1 μM pyrilamine. The binding reaction wascarried out for 50 minutes at room temperature and terminated byfiltration on Packard Unifilter GF/C (0.3% PEI) plates, followed by 2wash cycles with ice-cold assay buffer.

3. Data Analysis

Data derived from liquid scintillation counting were analyzed byiterative non-linear regression analysis with the use of the StatisticalAnalysis System (SAS): a program similar to “LIGAND” as described byMunson and Rodbard (Anal. Biochem. 1980, 107, 220-239). Fitting wasperformed according to formulae described by Feldman (Anal. Biochem.1972, 48, 317-338). IC₅₀, nH and K_(i) values were expressed asgeometrical mean. For receptors with a low affinity for the testcompound, where the highest tested compound concentration inhibited lessthan 30% of specific radioligand binding, K_(i)-values were determinedaccording to the equation of Cheng and Prusoff (Biochem. Pharmacol.1973, 22, 2099-2108) and expressed as greater than (>).

The results of the receptor binding studies are expressed as receptorbinding constants K_(i)(5-HT₆), K_(i)(D₂), K_(i)(α₁-adrenergic) andK_(i)(H₁), respectively, as described herein before, and given in tableI.

In these tests, the compounds according to the invention exhibit verygood affinities for the 5-HT₆ receptor (K₁<500 nM or <100 nM or <50 nMor <20 nM and frequently <10 nM). Furthermore those compounds bindselectively to the 5-HT₆ receptor, as compared to the affinity for theD₂, the α₁-adrenergic or the H₁ receptors. These compounds exhibitlittle affinities for the D₂, α₁-adrenergic or H₁ receptors (K_(i)>500nM or >1000 nM and frequently >10000 nM).

Example 1: Ki (5HT₆)<10 nM

Example 5: Ki (5HT₆)<50 nM

Example 6: Ki (5HT₆)<50 nM

Example 7: Ki (5HT₆)<50 nM

Example 8: Ki (5HT₆)<500 nM

Example 9: Ki (5HT₆)<500 nM

Example 10: Ki (5HT₆)<50 nM

Example 11: Ki (5HT₆)<500 nM

Example 12: Ki (5HT₆)<50 nM

Example 13: Ki (5HT₆)<50 nM

Example 14: Ki (5HT₆)<100 nM

Example 15: Ki (5HT₆)<500 nM

Example 16: Ki (5HT₆)<500 nM

Example 17: Ki (5HT₆)<10 nM

Example 18: Ki (5HT₆)<10 nM

Example 24: Ki (5HT₆)<10 nM

Example 25: Ki (5HT₆)<10 nM

Example 26: Ki (5HT₆)<10 nM

Example 27: Ki (5HT₆)<50 nM

Example 28: Ki (5HT₆)<50 nM

Example 29: Ki (5HT₆)<10 nM

Example 30: Ki (5HT₆)<10 nM

Example 31: Ki (5HT₆)<50 nM

Example 32: Ki (5HT₆)<10 nM

Example 33: Ki (5HT₆)<10 nM

Example 34: Ki (5HT₆)<10 nM

Example 35: Ki (5HT₆)<10 nM

Example 36: Ki (5HT₆)<10 nM

Example 37: Ki (5HT₆)<10 nM

Example 38: Ki (5HT₆)<10 nM

Example 39: Ki (5HT₆)<500 nM

Example 40: Ki (5HT₆)<50 nM

Example 41: Ki (5HT₆)<10 nM

Example 42: Ki (5HT₆)<10 nM

Example 43: Ki (5HT₆)<500 nM

Example 45: Ki (5HT₆)<10 nM

Example 46: Ki (5HT₆)<10 nM

Example 47: Ki (5HT₆)<10 nM

Example 48: Ki (5HT₆)<10 nM

Example 49: Ki (5HT₆)<10 nM

Example 51: Ki (5HT₆)<10 nM

Example 52: Ki (5HT₆)<50 nM

Example 53: Ki (5HT₆)<10 nM

Example 54: Ki (5HT₆)<10 nM

Example 55: Ki (5HT₆)<10 nM

Example 56: Ki (5HT₆)<50 nM

Example 57: Ki (5HT₆)<10 nM

Example 58: Ki (5HT₆)<10 nM

Example 59: Ki (5HT₆)<10 nM

Example 60: Ki (5HT₆)<10 nM

Example 61: Ki (5HT₆)<10 nM

Example 62: Ki (5HT₆)<10 nM

Example 63: Ki (5HT₆)<10 nM

Example 64: Ki (5HT₆)<10 nM

Example 65: Ki (5HT₆)<10 nM

Example 66: Ki (5HT₆)<10 nM

Example 67: Ki (5HT₆)<10 nM

Example 68: Ki (5HT₆)<10 nM

Example 69: Ki (5HT₆)<10 nM

Example 70: Ki (5HT₆)<10 nM

Example 71: Ki (5HT₆)<10 nM

Example 72: Ki (5HT₆)<10 nM

Example 73: Ki (5HT₆)<10 nM

Example 74: Ki (5HT₆)<50 nM

Example 75: Ki (5HT₆)<50 nM

Example 76: Ki (5HT₆)<50 nM

Example 77: Ki (5HT₆)<50 nM

Example 78: Ki (5HT₆)<50 nM

Example 79: Ki (5HT₆)<50 nM

Example 80: Ki (5HT₆)<50 nM

Example 81: Ki (5HT₆)<50 nM

Example 82: Ki (5HT₆)<10 nM

Example 83: Ki (5HT₆)<10 nM

Example 84: Ki (5HT₆)<50 nM

Example 85: Ki (5HT₆)<500 nM

Example 86: Ki (5HT₆)<500 nM

Example 87: Ki (5HT₆)<50 nM

Example 88: Ki (5HT₆)<500 nM

Example 89: Ki (5HT₆)<10 nM

Example 90: Ki (5HT₆)<50 nM

Example 91: Ki (5HT₆)<50 nM

Example 92: Ki (5HT₆)<10 nM

Example 93: Ki (5HT₆)<10 nM

Example 94: Ki (5HT₆)<10 nM

Example 95: Ki (5HT₆)<10 nM

Example 96: Ki (5HT₆)<50 nM

Example 97: Ki (5HT₆)<10 nM

Example 98: Ki (5HT₆)<50 nM

Example 99: Ki (5HT₆)<500 nM

Example 100: Ki (5HT₆)<10 nM

Example 101: Ki (5HT₆)<10 nM

Example 106: Ki (5HT₆)<10 nM

3. Determination of the Metabolic Stability

The metabolic stability of the compounds of the invention was determinedin the following assay by analyzing the microsomal half-life. The testsubstances are incubated in a concentration of 0.5 μM as follows:

0.5 μM test substance is preincubated together with liver microsomes ofvarious species (0.25 mg of protein/ml) in 0.05M potassium phosphatebuffer pH 7.4 in microtiter plates at 37° C. for 5 min. The reaction isstarted by adding NADPH (1 mg/mL). Aliquots are taken after 0, 5, 10,15, 20 and 30 min, and the reaction is stopped with the same volume ofacetonitrile and cooled down. The remaining test compound concentrationsare being determined by liquid chromatography—mass spectrometryanalysis. Intrinsic clearance values are calculated using theelimination rate constant of test compound depletion.

1-30. (canceled)
 31. A non-prophylactic method for treating acute orchronic signs, symptoms and/or malfunctions of an addictive disease,said method comprising administering an effective amount of aN-Phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide orbenzenesulfonyl-phenyl-(piperazine or homopiperazine) of formula (I) or(I′)

wherein X is a bond or a group N—R⁴; R¹ is hydrogen or methyl; R² ishydrogen or methyl; R³ is hydrogen, C₁-C₃ alkyl, fluorine, C₁-C₂ alkoxyor fluorinated C₁-C₂ alkoxy; R⁴ is hydrogen, C₁-C₄ alkyl, C₃-C₄cycloalkyl, or C₃-C₄ cycloalkyl-CH₂—; R⁵ is hydrogen, fluorine,chlorine, C₁-C₂ alkyl, fluorinated C₁-C₂ alkyl, C₁-C₂ alkoxy orfluorinated C₁-C₂ alkoxy; R⁶ is hydrogen, fluorine or chlorine; and n is1 or 2, or a physiologically tolerated acid addition salt or an N-oxidethereof.
 32. The method of claim 31, wherein the addictive disease iscaused by the abuse of a psychotropic substance.
 33. The method of claim32, wherein the psychotropic substance is a sedative, an anxiolytic, ahypnotic, or a narcotic.
 34. The method of claim 32, wherein thepsychotropic substance is an opioid, cocaine, nicotine, alcohol, asubstance which interacts with the GABA chloride channel complex, asedative, a hypnotic, a tranquilizer, lysergic acid diethylamide, acannabinoid, a psychomotor stimulant, an amphetamine or amphetamine-likesubstance, or caffeine.
 35. The method of claim 31, wherein theaddictive disease is an addiction to gaming.
 36. The method of claim 31,wherein the addictive disease is an addiction to gambling, a computer orvideo game addiction, or an internet addiction.
 37. The method of claim31, wherein X is a group N—R⁴.
 38. The method of claim 31, wherein nis
 1. 39. The method of claim 31, wherein R³ is methyl or methoxy. 40.The method of claim 31, wherein R⁴ is hydrogen.
 41. The method of claim31, wherein R⁵ is methyl, methoxy or difluoromethoxy.
 42. The method ofclaim 31, wherein R⁶ is hydrogen.
 43. The method of claim 31, wherein Xis a bond or a group N—R⁴; R¹ is hydrogen or methyl; R² is hydrogen; R³is hydrogen, C₁-C₂ alkyl, or C₁-C₂ alkoxy; R⁴ is hydrogen, methyl,ethyl, n-propyl, isopropyl or cyclopropylmethyl; R⁵ is hydrogen, methylor methoxy; R⁶ is hydrogen; and n is 1 or
 2. 44. The method of claim 31,wherein the OCHF₂-radical in formula I is located on the benzene ring inthe ortho-position with respect to X.
 45. The method of claim 31,wherein the OCHF₂-radical in formula I is located on the benzene ring inthe meta-position with respect to X.
 46. The method of claim 31, whereinthe OCHF₂-radical in formula I is located on the benzene ring in thepara-position with respect to X.
 47. The method of claim 31, wherein thecompound of formula (I) or (I′) is selected from the group consistingof:N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide;1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-piperazine;N-(2-difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamide;N-(2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamide;N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzene-sulfonamide;N-(4-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-cyclopropylmethyl-N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-cyclopropylmethyl-N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzene-sulfonamide;N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-4,N-dimethyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-N-methyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzene-sulfonamide;N-(4-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;3-[1,4]diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide;3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamide;N-(2-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-4-methoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-N-isopropyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-N-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;1-[3-(3-difluoromethoxy-benzenesulfonyl)-phenyl]-piperazine;1-[3-(3-difluoromethoxy-benzenesulfonyl)-phenyl]-4-methyl-piperazine;1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine;1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-4-methyl-piperazine;1-[5-(3-difluoromethoxy-4-methoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine;N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamide;N-(3,4-bis-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(3,4-bis-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(5-chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(5-difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(5-chloro-2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(5-chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(5-difluoromethoxy-2-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(5-difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(3,4-bis-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(5-chloro-2-difluoromethoxy-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-4-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((R)-3-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((S)-3-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide;N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(5-chloro-2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N(2-difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(5-difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(5-difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-4-methyoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(4-difluoromethoxy-3-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(4-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(3-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(4-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide;3-[1,4]diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide;3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamide;N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide;N-(3-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide;N-(5-difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-ylbenzenesulfonamide;N-(5-difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-N-methyl-3-piperazin-1-ylbenzenesulfonamide;N-(5-difluoromethoxy-2-methylphenyl)-4-fluoro-3-piperazin-1-ylbenzenesulfonamide;N-(5-difluoromethoxy-2-methylphenyl)-4-fluoro-N-methyl-3-piperazin-1-ylbenzenesulfonamide; and the physiologically tolerated acid additionsalts thereof and the N-oxides thereof.
 48. The method of claim 31,wherein the compound of formula (I) or (I′) is selected from the groupconsisting of:N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamide;N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide;N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide;N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-ylbenzenesulfonamide; and the physiologically tolerated acid additionsalts thereof and the N-oxides thereof.
 49. The method of claim 31,wherein the compound of formula (I) or (I′) isN-(2-difluoromethoxy-4-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamide,or a physiologically tolerated acid addition salt or N-oxide thereof.50. The method of claim 31, wherein the compound of formula (I) or (I′)isN-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,or a physiologically tolerated acid addition salt or N-oxide thereof.